Synthetic heparin monosaccharides

ABSTRACT

Preparation of synthetic monosaccharides, for use in the preparation of synthetic heparinoids.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/488,677 (U.S. Pat. No. 7,541,445), which is a National Phaseapplication under 35 U.S.C. §371 of International Application No.PCT/AU02/01228, filed Sep. 6, 2002, and claims the benefit of AustralianApplication No. PR 7587, filed Sep. 7, 2001, the disclosures of whichare incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

This invention is directed to intermediates, and processes for thechemical synthesis of AT-III binding heparin or heparinoid,pentasaccharides.

BACKGROUND ART

Vascular thrombosis is a cardiovascular disease indicated by the partialor total occlusion of a blood vessel by a clot containing blood cellsand fibrin. In arteries, it results predominantly from plateletactivation and leads to heart attack, angina or stroke, whereas venousthrombosis results in inflammation and pulmonary emboli. The coagulationof blood is the result of a cascade of events employing various enzymescollectively known as activated blood-coagulation factors. Heparin, apowerful anticoagulant has been used since the late 1930's in thetreatment of thrombosis. In its original implementation, toleranceproblems were noted and so reduced dosage was suggested to reducebleeding and improve efficacy. In the early 1970's, clinical trials didindeed indicate acceptable tolerance was obtainable whilst stillpreserving antithrombotic activity. Unfractioned heparin (UFH) isprimarily used as an anticoagulant for both therapeutic and surgicalindications, and is usually derived from either bovine lung or porcinemucosa. Amongst the modern uses of unfractioned heparin are themanagement of unstable angina, an adjunct to chemotherapy andanti-inflammatory treatment, and as a modulation agent for growthfactors and treatment of haemodynamic disorders.

In the late 1980's, the development of low molecular weight heparins(LMWHs) led to improvements in antithrombotic therapy. LMWHs are derivedfrom UFH by such processes as; chemical degradation, enzymaticdepolymerisation and γ-radiation cleavage. This class of heparins hasrecently been used for treatment of trauma related thrombosis. Ofparticular interest is the fact that their relative effects on plateletsare minimal compared to heparin, providing an immediate advantage whentreating platelet compromised patients. The degree of depolymerisationof UFH can be controlled to obtain LMWH of different lengths. Dosagerequirements for the treatment of deep vein thrombosis (DVT) aresignificantly reduced when employing LMWH as opposed to UFH, although ingeneral the efficacy of both therapeutics seems to be comparable. Inaddition, LMWH can be effective as an alternative therapeutic forpatients who have developed a sensitivity to UFH. Unfortunately, therehas recently been a great deal of concern in the use of LMWH due to theperceived potential for cross-species viral contamination as a result ofthe animal source of the parent UFH.

One way of avoiding the possibility of cross-species contamination, isto prepare heparins by chemical synthesis. This method would alsoprovide the opportunity to develop second generation heparins orheparinoids, that can be tailored to target particular biological eventsin the blood coagulation cascade.

An investigation to determine the critical structural motif required foran important binding event in a coagulation cascade involving heparin,dates back to the 1970's. Some structural features of heparin weredefined, but the binding domains of interest remained essentiallyundefined. Research conducted by Lindahl and co-workers¹ and separatelyby Choay and co-workers² eventually led to the determination that apentasaccharide sequence constituted the critical binding domain for thepro-anticoagulant cofactor, antithrombin III (AT-III). Afterdetermination of the critical heparin sugar sequence, complete chemicalsyntheses were embarked upon to further prove the theories. Completesyntheses of the pentasaccharide binding domain were completed atsimilar times by Sinay and co-workers³ and by Van Boeckel andco-workers⁴.

Significant difficulties were encountered during both these reportedsyntheses. The synthesis by Van Boeckel and co-workers provided a methodon reasonable scale (156 mg's of final product) and with improved yieldscompared to the Sinay synthesis, but still only provided an overallyield of 0.22%, (compared with 0.053% for the Sinay synthesis). Oneparticular problem encountered during the final deprotection, was theintermolecular reaction of the hemiacetal (the reducing endfunctionality of the sugar), which led to the formation dimers andtrimers. To reduce the likelihood of this occurring, an α-methylglycoside of the pentasaccharide was synthesised. The structures ofinterest are represented immediately below, wherein I represents thehemiacetal form, and II represents the α-methylglycoside form.

As mentioned, studies have determined that the significant biologicalevent in preventing thrombosis is the binding of a pentasaccharidesequence⁵ of heparin, to heparin cofactor antithrombin III (AT-III). Aswell as pentasaccharide I, the important derivative II has also beenprepared by total synthesis⁶. Compound II has recently completed phaseIII clinical trials for the treatment of deep-vein thrombosis. Thefollowing patents display some relevance to the present invention. U.S.Pat. No. 4,401,662 claims composition of matter on the pentasaccharideAT-III binding sequence of heparin as does U.S. Pat. No. 4,496,550.Patents EP 0,084,999 and U.S. Pat. No. 4,818,816 detail syntheticmethodologies towards pentasaccharide I, and derivative II.

OBJECT OF THE INVENTION

It is an object of the invention to provide a synthetic preparation forheparin pentasaccharides, and intermediates thereof, and to novelintermediates for heparin pentasaccharides, and to novel heparinpentasaccharides.

The present invention provides composition of matter of intermediates,and a process for the synthesis, of AT-III binding heparins andheparinoids. What this entails is a stepwise synthetic process employingmonosaccharide building blocks.

The nature of the AT-III binding pentasaccharide is such, that undercursory analysis of the individual monomeric units constituting thepentasaccharide, we note that each is distinct from the others.Secondly, we can see that there is an alternating stereospecificity inregard to the glycosidic linkages (below).

In a synthesis, the difference evident in each block requires that eachindividual monomer used in the synthesis will need a differentprotecting group pattern. In light of this, it is essential in thesynthesis of the above pentasaccharide that a protecting group strategyis carefully conceived. As can be seen, the pentasaccharide displaysO-sulphation, N-sulphation, there are free hydroxyl groups, and thereare stereospecific glycosidic linkages.

Therefore, a protection strategy is required such that (1) sulphationcan be effected at the required sites, whilst leaving some hydroxylgroups unsulphated (note that due to the chemical lability of N- andO-sulphates, sulphation needs to be effected late in the synthesis), (2)a protection strategy is required that assists in effecting theappropriate glycosidic linkage and (3) a protection strategy is requiredthat enables the correct (in terms of regio- and stereoisomerism)glycosidic linkages to be formed. α-Glycosidic linkages are typicallygenerated by the use of what are known as non-participating protectinggroups, whilst β-linkages are effected by participating protectinggroups. Some N- and O-participating and non-participating protectinggroups are known to the art (the art being considered carbohydratechemistry). It is also well known to the art that the kind of protectinggroups employed can effect the reactivity of the building block. Theculmination of these requirements are demonstrated in the exemplarybuilding block C below, which displays the kind of characteristicsrequired to effect the synthesis of heparin oligosaccharides.

In exemplary building block C, X is a leaving group suitable of reactingwith another monomer or acceptor, to form an interglycosidic linkage; R¹is a non-participating amino protecting group so as to effect anα-linkage upon activation of X followed by coupling to an appropriateacceptor; R² and R⁴ can be similarly protected to allow for eventualO-sulphation, whilst R³ is required to be differentially protected so asto allow the formation of an acceptor hydroxyl group to couple thisblock to the next in the chain. The building blocks shown immediatelybelow exemplify the kind of derivatised monosaccharides required toeffect the synthesis of heparin AT-III binding pentasaccharides.

The protecting groups represented by ‘R_(S)’ shown above are sites thatwill eventually require O-sulphation, the protecting groups representedby ‘R_(H)’ need to be orthogonal to ‘R_(S)’ and represents sites thatwill eventually become hydroxyl groups. The substituents ‘X₁’ and ‘X₂’represent leaving groups that are activated to react with anothersuitable protected building block to form a glycosidic linkage, and, inthe case of X₁, may also be derivatised as alkyl glycosides orsubstituted with a group suitable to allow conjugation to a support fordrug delivery. The ‘R_(L)’ groups are protecting groups orthogonal toboth ‘R_(S)’ and ‘R_(H)’, and represent sites through which chainelongation via glycosylation occurs. ‘R’ is representative of either aprotected or latent carboxylate function. The ‘R_(A)’ groups arenon-participating amino protecting groups that enable α-linkages to beformed while the ‘R_(B)’ groups may be either a participating ornon-participating amino protecting group. There is another level ofcomplexity to be added to the synthesis in as much as the protectinggroups in blocks D and B that are indicated by the boxes, need to besuch that they allow for the formation of a β-glycosidic linkage. Thismay require a two stage protection at the indicated sites, i.e., aprotection followed by deprotection and subsequent reprotection with adifferent protecting group. The initial protection is required to effectthe correct stereochemistry in a glycosylation, and second stageprotection to allow for the correct sulphation pattern.

As is evident, the pentasaccharide can be constructed in a variety ofdifferent ways; blocks B and A can be coupled, blocks E and D can becoupled, block C can be coupled to either, and the resulting dimer andtrimer can finally be coupled to form the pentasaccharide.Alternatively, each block can be added sequentially and so on. There area number of alternative coupling sequences that can be easily conceivedand the choice made in regard to this, in itself, has a marked effect onthe synthetic methodologies that will finally be employed, and thereforeimpacts on the overall success of the synthesis.

In one aspect the invention provides for a monosaccharide building blockin the D-glucopyrano configuration, for the preparation of syntheticheparinoids, said building block of General Formula I,

wherein, X₁ includes but is not limited to: hydroxy, alkoxy, aryloxy,benzyloxy, substituted benzyloxy; thioalkyl, thioaryl, halogen,trichloroacetimidoyl, phosphate and related phosphate ester type leavinggroups, or other suitable leaving group; a ^(t)butyldiphenylsilyloxy orother such substituted silyloxy protecting group; a lipoaminoacid orother such group suitable for conjugation to delivery systems or solidsupports; and the stereochemistry may be alpha or beta; other suitablegroups will be known to those skilled in the art, R_(A) includes but isnot limited to: an azido function, an amine; an NH-Dde, NH-DTPM,NH-Fmoc, NH-Boc, NH-Cbz, NH-Troc, N-phthalimido; or, other such suitableprotected amino functions known to those skilled in the art, R_(H) is abenzyl or, substituted benzyl protecting group, allyl, allyloxycarbonyl,or R_(H1) and R_(A) can combine together to form a cyclic carbamate;R_(L) includes but is not limited to: a H atom; a levulinoyl,chloroacetyl, 4-acetoxybenzoyl, 4-acetamidobenzoyl, 4-azidobenzoyl, orother substituted benzoyl type protecting group; a benzyl group, a4-acetoxybenzyl, 4-acetamidobenzyl or other such suitable substitutedbenzyl type protecting group; γ-aminobutyryl,4-N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-butyryl,4-N-[1-(1,3-dimethyl-2,4,6(1H,3H,5H)-trioxopyrimidin-5-ylidene)methylamino]-butyryl,4-N-Alloc-butyryl, 4-N-Fmoc-butyryl, 4-N-Boc-butyryl type protectinggroups allyloxycarbonyl, allyl ether, carbonate type protecting groups;or R_(L) and R_(S1) can combine to form a benzylidene or substitutedbenzylidene ring; or, other such suitable protecting groups as known tothose skilled in the art, andR_(S) includes but is not limited to: 4-methoxyphenyl; substitutedbenzyl groups; alkylacyl, arylacyl or alkylarylacyl, and substitutedalkylacyl, arylacyl or alkylarylacyl protecting groups; carbonateprotecting groups, a ^(t)butyldiphenylsilyloxy or other such substitutedsilyloxy protecting group, allyl, methoxymethyl, methoxyethyl,benzyloxymethyl; or, other suitable protecting groups as known to thoseskilled in the art.

Alternatively R_(L) and R_(S) can combine to form a benzylidene orsubstituted benzylidene ring.

In a second aspect the invention provides for a monosaccharide buildingblock in the L-idopyrano conformation, for the preparation of syntheticheparinoids, said building block of General Formula II,

wherein, X₂ includes but is not limited to: a hydroxyl group; thioalkyl,thioaryl, halogen, trichloroacetimidoyl, phosphate and related phosphateester type leaving groups, or other suitable leaving group; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; and the stereochemistry may be alpha or beta; other suitablegroups will be known to those skilled in the art,R_(S) is defined as in General Formula I,R_(H) is defined as in General Formula I,R_(L) is defined as in General Formula I, andR_(E) includes but is not limited to: methyl, C₂-C₅ alkyl; substitutedalkyl; or, benzyl and substituted benzyl groups; other suitable groupswill be known to those skilled in the art. Or,R_(H) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, allyloxycarbonyl;R_(S) is selected from the group consisting of 4-methoxyphenyl;substituted benzyl groups; alkylacyl, arylacyl or alkylarylacyl, andsubstituted alkylacyl, arylacyl or alkylarylacyl protecting groups;carbonate protecting groups; a ^(t)butyldiphenylsilyloxy or other suchsubstituted silyloxy protecting group allyl, methoxymethyl,methoxyethyl, benzyloxymethyl;R_(E) is selected from the group consisting of methyl, C₂-C₅ alkyl;substituted alkyl, C₃-C₅ alkenyl; or, benzyl and substituted benzylgroups;R_(L) is selected from a H atom; a levulinoyl, chloroacetyl,4-acetoxybenzoyl, 4-acetamidobenzoyl, 4-azidobenzoyl, or othersubstituted benzoyl type protecting group; a benzyl group, a4-acetoxybenzyl, 4-acetamidobenzyl or other such suitable substitutedbenzyl type protecting group; γ-aminobutyryl,4-N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-butyryl,4-N-[1-(1,3-dimethyl-2,4,6(1H,3H,5H)-trioxopyrimidin-5-ylidene)methylamino]-butyryl,4-N-Alloc-butyryl, 4-N-Fmoc-butyryl, 4-N-Boc-butyryl type protectinggroups; allyloxycarbonyl, allyl ether, carbonate type protecting groups;X₂ is selected from a hydroxyl group, thioalkyl, thioaryl, halogen,imidoyl, phosphate and related phosphate ester type leaving groups, a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; and the stereochemistry may be alpha or beta.

In a third aspect the invention provides for a monosaccharide buildingblock in the L-idopyrano configuration, for the preparation of syntheticheparinoids, said building block of General Formula III,

wherein, X₂ is defined as in General Formula II,R_(S) is defined as in General Formula II,R_(H) is defined as in General Formula I,R_(L) is defined as in General Formula I, andR_(M) includes but is not limited to a p-methoxyphenyl protecting groupor other suitable oxidatively labile protecting group; a trityl group;or, other such suitable protecting groups as known to those skilled inthe art.

In a fourth aspect the invention provides for a monosaccharide buildingblock in the D-glucopyrano configuration for the preparation ofsynthetic heparinoids, said building block of General Formula IV,

wherein, X₂ is defined as in General Formula II,R_(B) includes but is not limited to: an azido function, an amine; anNH-Dde or NH-DTPM group; or other suitably protected amino functions asknown to those skilled in the art, or R_(S) (adjacent R_(B)) and R_(B)can combine together to form a cyclic carbamate;R_(S) (adjacent R_(B)) is selected from the group consisting of4-methoxyphenyl; substituted benzyl groups; alkylacyl, arylacyl oralkylarylacyl, and substituted alkylacyl, arylacyl or alkylarylacylprotecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup allyl, methoxymethyl, methoxyethyl, benzyloxymethyl, or R_(S4) andR_(B) may be combined to form a cyclic carbamate;R_(S) (adjacent the oxygen) is selected from the group consisting of4-methoxyphenyl; substituted benzyl groups; alkylacyl, arylacyl oralkylarylacyl, and substituted alkylacyl, arylacyl or alkylarylacylprotecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup, allyl, methoxymethyl, methoxyethyl, benzyloxymethyl.

In a fifth aspect the invention provides for a monosaccharide buildingblock in the D-glucuronate configuration for the preparation ofsynthetic heparinoids, said building block of General Formula V,

wherein, X₂ is as defined in General Formula II,R_(P) includes but is not limited to: 4-methoxyphenyl; substitutedbenzyl groups; alkylacyl, arylacyl and alkylarylacyl, or substitutedalkylacyl, arylacyl and alkylarylacyl protecting groups; carbonateprotecting groups; or, other suitable protecting groups as known tothose skilled in the art.R_(L) is defined as in General Formula I, andR_(E) is defined as in General Formula II.

In a sixth aspect the invention provides for a monosaccharide buildingblock in the D-glucopyrano configuration for the preparation ofsynthetic heparinoids, said building block of General Formula VI,

wherein, X₂ is as defined as in General Formula II,R_(B) is defined as in General Formula IV,R_(H) may be selected independently and are defined as in GeneralFormula I, andR_(S) is defined as in General Formula I, or, whereinR_(H) (adjacent the ORs moiety) is selected from the group consisting ofbenzyl or substituted benzyl protecting group, allyl, allyloxycarbonyl;R_(H) (adjacent the Rb moiety) is selected from the group consisting ofbenzyl or substituted benzyl protecting group, allyl, allyloxycarbonyl,or this R_(H) and R_(B) independently can combine together to form acyclic carbamate;R_(S) is selected from the group consisting of 4-methoxyphenyl;substituted benzyl groups; alkylacyl, arylacyl or alkylarylacyl; andsubstituted alkylacyl, arylacyl or alkylarylacyl protecting groups;carbonate protecting groups; a ^(t)butyldiphenylsilyloxy or other suchsubstituted silyloxy protecting group allyl, methoxymethyl,methoxyethyl, benzyloxymethyl, or R_(S5) and R_(H) can be combined toform a cyclic acetal or ketal moiety;R_(B) is selected from the group consisting of an azido function, anamine; an NH-Dde or NH-DTPM group, or R_(H) (adjacent the R_(B)) andR_(B) can combine together to form a cyclic carbamate;X₂ is selected from a hydroxyl group; thioalkyl, thioaryl, halogen,trichloroacetimidoyl, phosphate and related phosphate ester type leavinggroups, a ^(t)butyldiphenylsilyloxy or other such substituted silyloxyprotecting group; and the stereochemistry may be alpha or beta.

In a seventh aspect the invention provides for a monosaccharide buildingblock in the D-glucopyrano configuration for the preparation ofsynthetic heparinoids, said building block of General Formula VII,

wherein, X₁ is defined as in General Formula I,R_(L) is defined as in General Formula I, andR_(S) is defined as in General Formula I. R_(L) and R_(S) may alsotogether combine to form a benzylidene or substituted benzylidene ring,orX₁ is selected from the group consisting of hydroxy, alkoxy, aryloxy,benzyloxy, substituted benzyloxy, thioalkyl, thioaryl, halogen,trichloroacetimidoyl, phosphate and related phosphate ester type leavinggroups, a ^(t)butyldiphenylsilyloxy or other such substituted silyloxyprotecting group; a lipoaminoacid or other such group suitable forconjugation to delivery systems or solid supports; and thestereochemistry may be alpha or beta;R_(L) is selected from an H atom; a levulinoyl, chloroacetyl,4-acetoxybenzoyl, 4-acetamidobenzoyl, 4-azidobenzoyl, or othersubstituted benzoyl type protecting group; a benzyl group, a4-acetoxybenzyl, 4-acetamidobenzyl or other such suitable substitutedbenzyl type protecting group; γ-aminobutyryl,4-N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-butyryl,4-N-[1-(1,3-dimethyl-2,4,6(1H,3H,5H)-trioxopyrimidin-5-ylidene)methylamino]-butyryl,4-N-Alloc-butyryl, 4-N-Fmoc-butyryl, 4-N-Boc-butyryl type protectinggroups; allyloxycarbonyl, allyl ether, and carbonate type protectinggroups;R_(S) is selected from the group consisting of 4-methoxyphenyl,4-methoxybenzyl; substituted benzyl groups; alkylacyl, arylacyl oralkylarylacyl, and substituted alkylacyl, arylacyl or alkylarylacylprotecting groups; carbonate protecting groups; andtert-Butyldiphenylsilyl;R_(L) and R_(S) may also together combine to form an alkylidene,isopropylidene, benzylidene or substituted benzylidene ring.

In an eighth aspect the invention provides for a disaccharide buildingblock for the preparation of synthetic heparinoids, said building blockof General Formula VIII,

wherein, X₁ is defined as in General Formula I,R_(H1) is defined as being selected from R_(H) of General Formula I,with the addition that R_(H1) and R_(A) can combine together to form acyclic carbamate,R_(A) is defined as in General Formula I, with the addition that R_(H1)and R_(A) can combine together to form a cyclic carbamateR_(S) is defined as in General Formula I,R_(H) is defined as in General Formula I,R_(L) is defined as in General Formula I, andR_(E) is defined as in General Formula II, orX₁ is selected from the group consisting of hydroxy, alkenyloxy, alkoxy,aryloxy, benzyloxy, substituted benzyloxy, thioalkyl, thioaryl, halogen,imidoyl, phosphate and related phosphate ester type leaving groups, a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; a lipoaminoacid or other such group suitable for conjugation todelivery systems or solid supports; and the stereochemistry may be alphaor beta;R_(H) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, allyloxycarbonyl;R_(H1) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, allyloxycarbonyl, or R_(H1) and R_(A)can combine together to form a cyclic carbamate;R_(A) is selected from the group consisting of an azido function, anamine; an NH-Dde, NH-DTPM, NH-Fmoc, NH-Boc, NH-Troc, N-phthalimido,NH—Ac, NH-allyloxycarbonyl; or R_(H), and R_(A) can combine together toform a cyclic carbamate;R_(S) (on block A) is selected from the group consisting of4-methoxyphenyl; substituted benzyl groups; alkylacyl, arylacyl oralkylarylacyl, and substituted alkylacyl, arylacyl or alkylarylacylprotecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup, allyl, methoxymethyl, methoxyethyl, benzyloxymethyl or benzoyl;R_(S) (on block B) is selected from the group consisting of4-methoxyphenyl; substituted benzyl groups; alkylacyl, arylacyl oralkylarylacyl, and substituted alkylacyl, arylacyl or alkylarylacylprotecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; allyl, methoxymethyl, methoxyethyl, benzyloxymethyl;R_(E) is selected from the group consisting of methyl, C₂-C₅ alkyl;substituted alkyl, C₃-C₅ alkenyl; or, benzyl and substituted benzylgroups;R_(L) is selected from an H atom; a levulinoyl, chloroacetyl,4-acetoxybenzoyl, 4-acetamidobenzoyl, 4-azidobenzoyl, or othersubstituted benzoyl type protecting group; a benzyl group, a4-acetoxybenzyl, 4-acetamidobenzyl or other such suitable substitutedbenzyl type protecting group; γ-aminobutyryl,4-N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-butyryl,4-N-[1-(1,3-dimethyl-2,4,6(1H,3H,5H)-trioxopyrimidin-5-ylidene)methylamino]-butyryl,4-N-Alloc-butyryl, 4-N-Fmoc-butyryl, 4-N-Boc-butyryl type protectinggroups; allyloxycarbonyl, allyl ether, and carbonate type protectinggroups.

In a ninth aspect the invention provides for a disaccharide buildingblock for the preparation of synthetic heparinoids, said building blockof General Formula IX,

wherein, X₁ is as defined as in General Formula I,R_(A) is defined as in General Formula XIII,R_(H1) is defined as in General Formula XIII,R_(S) is defined as in General Formula I,R_(L) is defined as in General Formula I, andR_(M) is defined as in General Formula III, or, alternatively,X₁ is selected from the group consisting of hydroxy, alkenyloxy, alkoxy,aryloxy, benzyloxy, substituted benzyloxy; thioalkyl, thioaryl, halogen,imidoyl, phosphate and related phosphate ester type leaving groups, a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; a lipoaminoacid or other such group suitable for conjugation todelivery systems or solid supports; and the stereochemistry may be alphaor beta;R_(A) is selected from the group consisting of an azido function, anamine; an NH-Dde, NH-DTPM, NH-Fmoc, NH-Boc, NH-Troc, N-phthalimido,NH—Ac, NH-Allyloxycarbonyl; or R_(H1) and R_(A) can combine together toform a cyclic carbamate;R_(S) (on block A) is selected from the group consisting of4-methoxyphenyl; substituted benzyl groups; alkylacyl, arylacyl oralkylarylacyl, and substituted alkylacyl, arylacyl or alkylarylacylprotecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; allyl, methoxymethyl, methoxyethyl, and benzyloxymethyl;R_(S) (on block B) is selected from the group consisting of4-methoxyphenyl; substituted benzyl groups; alkylacyl, arylacyl oralkylarylacyl, and substituted alkylacyl, arylacyl or alkylarylacylprotecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; allyl, methoxymethyl, methoxyethyl, and benzyloxymethyl;R_(H) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, and allyloxycarbonyl;R_(H1) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, and allyloxycarbonyl, or R_(H1) andR_(A) can combine together to form a cyclic carbamate;R_(M) is selected from a p-methoxyphenyl or p-methoxybenzyl protectinggroup or other suitable oxidatively labile protecting group; and atrityl group;or R_(M) and R_(L) are combined together to form an isopropylidene,benzylidene, substituted benzylidene, cyclohexylidene or other acetal orketal protecting group; orR_(L) is selected from an H atom; a levulinoyl, chloroacetyl,4-acetoxybenzoyl, 4-acetamidobenzoyl, 4-azidobenzoyl, or othersubstituted benzoyl type protecting group; a benzyl group, a4-acetoxybenzyl, 4-acetamidobenzyl or other such suitable substitutedbenzyl type protecting group; γ-aminobutyryl,4-N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-butyryl,4-N-[1-(1,3-dimethyl-2,4,6(1H,3H,5H)-trioxopyrimidin-5-ylidene)methylamino]-butyryl,4-N-Alloc-butyryl, 4-N-Fmoc-butyryl, 4-N-Boc-butyryl type protectinggroups; allyloxycarbonyl, allyl ether, and carbonate type protectinggroups.

In a tenth aspect the invention provides for a disaccharide buildingblock for the preparation of synthetic heparinoids, said building blockof General Formula X,

wherein, X₂ is as defined in General Formula II,R_(S1) is defined as being selected from R_(S) of General Formula I,with the addition that R_(S1) and R_(B) can combine together to form acyclic carbamate.R_(B) is defined as in General Formula IV, with the addition that R_(S1)and R_(B) can combine together to form a cyclic carbamate.R_(S) is defined as in General Formula I,R_(P) are defined as in General Formula V,R_(L) is defined as in General Formula I, andR_(E) is defined as in General Formula II, orX₂ is selected from the group consisting of hydroxy, alkenyloxy, alkoxy,aryloxy, benzyloxy, substituted benzyloxy; thioalkyl, thioaryl, halogen,imidoyl, phosphate and related phosphate ester type leaving groups, a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; a lipoaminoacid or other such group suitable for conjugation todelivery systems or solid supports; and the stereochemistry may be alphaor beta;R_(S) is selected from the group consisting of 4-methoxyphenyl;substituted benzyl groups; alkylacyl, arylacyl or alkylarylacyl, andsubstituted alkylacyl, arylacyl or alkylarylacyl protecting groups;carbonate protecting groups; a ^(t)butyldiphenylsilyloxy or other suchsubstituted silyloxy protecting group allyl, methoxymethyl,methoxyethyl, and benzyloxymethyl;R_(S1) is selected from the group consisting of 4-methoxyphenyl;substituted benzyl groups; alkylacyl, arylacyl or alkylarylacyl, andsubstituted alkylacyl, arylacyl or alkylarylacyl protecting groups;carbonate protecting groups; a ^(t)butyldiphenylsilyloxy or other suchsubstituted silyloxy protecting group allyl, methoxymethyl,methoxyethyl, and benzyloxymethyl, or R_(S1) andR_(B) may be combined to form a cyclic carbamate;

-   R_(E) is selected from the group consisting of methyl, C₂-C₅ alkyl;    substituted alkyl, C₃-C₅ alkenyl; or, benzyl and substituted benzyl    groups;    R_(B) is selected from the group consisting of an azido function, an    NH-Dde or NH-DTPM group, or R_(S4) and R_(B) can combine together to    form a cyclic carbamate;    R_(P) (adjacent O—R_(L)) is selected from the group consisting of    4-methoxyphenyl; benzyl, substituted benzyl groups; alkylacyl,    arylacyl and alkylarylacyl, or substituted alkylacyl, arylacyl and    alkylarylacyl protecting groups; and carbonate protecting groups;    R_(P) (adjacent the link to block C) is selected from the group    consisting of hydroxy, 4-methoxyphenyl; benzyl, substituted benzyl    groups; alkylacyl, arylacyl and alkylarylacyl, or substituted    alkylacyl, arylacyl and alkylarylacyl protecting groups; carbonate    protecting groups, silyl protecting groups, carbamate protecting    groups, and C₃-C₅ alkenyl;    R_(L) is selected from an H atom; a levulinoyl, chloroacetyl,    4-acetoxybenzoyl, 4-acetamidobenzoyl, 4-azidobenzoyl, or other    substituted benzoyl type protecting group; a 4-acetoxybenzyl,    4-acetamidobenzyl or other such suitable substituted benzyl type    protecting group; γ-aminobutyryl,    4-N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-butyryl,    4-N-[1-(1,3-dimethyl-2,4,6(1H,3H,5H)-trioxopyrimidin-5-ylidene)methylamino]-butyryl,    4-N-Alloc-butyryl, 4-N-Fmoc-butyryl, 4-N-Boc-butyryl type protecting    groups; allyloxycarbonyl, allyl ether, and carbonate type protecting    groups.

In an eleventh aspect the invention provides for a disaccharide buildingblock for the preparation of synthetic heparinoids, said building blockof General Formula XI,

wherein, X₂ is as defined in General Formula II,R_(P) are defined as in General Formula V,R_(E) is defined as in General Formula II,R_(B) is defined as in General Formula IV, with the addition that R_(B)and R_(H2) can combine to form a cyclic carbamate,R_(H2) is defined as being selected from R_(H) of General Formula I,with the addition that R_(B) and R_(H2) can combine to form a cycliccarbamate,R_(H) is defined as in General Formula I, andR_(S) is defined as in General Formula I, orX₂ is selected from a hydroxyl group; thioalkyl, thioaryl, halogen,trichloroacetimidoyl, phosphate and related phosphate ester type leavinggroups, a ^(t)butyldiphenylsilyloxy or other such substituted silyloxyprotecting group; and the stereochemistry may be alpha or beta;R_(P) (adjacent the O link) is selected from the group consisting of4-methoxyphenyl; benzyl, substituted benzyl groups; alkylacyl, arylacyland alkylarylacyl, or substituted alkylacyl, arylacyl and alkylarylacylprotecting groups; carbonate protecting groups;R_(P) (adjacent X₂) is selected from the group consisting of4-methoxyphenyl; benzyl, substituted benzyl groups; alkylacyl, arylacyland alkylarylacyl, or substituted alkylacyl, arylacyl and alkylarylacylprotecting groups; carbonate protecting groups, silyl protecting groups,carbamate protecting groups, and C₃-C₅ alkenyl;R_(E) is selected from the group consisting of methyl, C₂-C₅ alkyl;substituted alkyl, C₃-C₅ alkenyl; or, benzyl and substituted benzylgroups;R_(B) is selected from the group consisting of an azido function, anamine; an NH-Dde or NH-DTPM group, or R_(H2) and R_(B1) can combinetogether to form a cyclic carbamate;R_(H) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, and allyloxycarbonyl;R_(H2) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, allyloxycarbonyl, or R_(H2) and R_(B1)independently can combine together to form a cyclic carbamate;R_(S) is selected from the group consisting of 4-methoxyphenyl;4-methoxybenzyl, substituted benzyl groups; alkylacyl, benzoyl arylacylor alkylarylacyl, and substituted alkylacyl, 4-chlorobenzoyl, arylacylor alkylarylacyl protecting groups; allyloxycarbonyl, ethoxycarbonyl,tertbutoxycarbonyl, carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; allyl, methoxymethyl, methoxyethyl, and benzyloxymethyl; or R_(S)and R_(H) can be combined to form a cyclic acetal or ketal moiety.

In a twelfth aspect the invention provides for a disaccharide buildingblock for the preparation of synthetic heparinoids, said building blockof General Formula XII,

wherein, X₂ is as defined in General Formula II,R_(P) are defined as in General Formula V,R_(M) is defined as in General Formula III,R_(B) and R_(H2) are as defined in General Formula XI,R_(H) is defined as in General Formula I, andR_(S) is defined as in General Formula I, orX₂ is selected from a hydroxyl group; thioalkyl, thioaryl, halogen,trichloroacetimidoyl, phosphate and related phosphate ester type leavinggroups, a ^(t)butyldiphenylsilyloxy or other such substituted silyloxyprotecting group; and the stereochemistry may be alpha or beta;R_(P) (adjacent the O linking group) is selected from the groupconsisting of 4-methoxyphenyl; benzyl, substituted benzyl groups;alkylacyl, arylacyl and alkylarylacyl, or substituted alkylacyl,arylacyl and alkylarylacyl protecting groups; and carbonate protectinggroups;R_(P) (adjacent X₂) is selected from the group consisting of4-methoxyphenyl; benzyl, substituted benzyl groups; alkylacyl, arylacyland alkylarylacyl, or substituted alkylacyl, arylacyl and alkylarylacylprotecting groups; carbonate protecting groups, silyl protecting groups,carbamate protecting groups, and C₃-C₅ alkenyl;R_(B) is selected from the group consisting of an azido function, anamine; an NH-Dde or NH-DTPM group, or R_(H2) and R_(B1) can combinetogether to form a cyclic carbamate;R_(H) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, and allyloxycarbonyl;R_(H2) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, allyloxycarbonyl, or R_(H2) and R_(B1)independently can combine together to form a cyclic carbamate;R_(S) is selected from the group consisting of 4-methoxyphenyl;4-methoxybenzyl, substituted benzyl groups; alkylacyl, benzoyl, arylacylor alkylarylacyl, and substituted alkylacyl, 4-chlorobenzoyl, arylacylor alkylarylacyl protecting groups; allyloxycarbonyl, ethoxycarbonyl,tertbutoxycarbonyl, carbonate protecting groups; or is selected from thegroup consisting of 4-methoxyphenyl; substituted benzyl groups;alkylacyl, arylacyl or alkylarylacyl, and substituted alkylacyl,arylacyl or alkylarylacyl protecting groups; carbonate protectinggroups; a ^(t)butyldiphenylsilyloxy or other such substituted silyloxyprotecting group allyl, methoxymethyl, methoxyethyl, andbenzyloxymethyl;or R_(S) and R_(H) can be combined to form a cyclic acetal or ketalmoiety;R_(M) is selected from the group consisting of a p-methoxyphenylprotecting group or other suitable oxidatively labile protecting group;a trityl group.

In a thirteenth aspect the invention provides for a disaccharidebuilding block for the preparation of synthetic heparinoids, saidbuilding block of General Formula XIII,

wherein, X₂ is defined as in General Formula II,R_(B) and R_(S1) are defined as in General Formula X,R_(S) is defined as in General Formula I,R_(P) is defined as in General Formula V, andA includes but is not limited to; H, methoxy, methyl; other suitablesubstituents will be known to those in the art, orX₂ is selected from a hydroxyl group; thioalkyl, thioaryl, halogen,imidoyl, phosphate and related phosphate ester type leaving groups, a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; and the stereochemistry may be alpha or beta;R_(B) is selected from the group consisting of an azido function, anamine; an NH-Dde or NH-DTPM group, or R_(S4) and R_(B) can combinetogether to form a cyclic carbamate;R_(S) is selected from the group consisting of 4-methoxyphenyl;substituted benzyl groups; alkylacyl, arylacyl or alkylarylacyl, andsubstituted alkylacyl, arylacyl or alkylarylacyl protecting groups;carbonate protecting groups; a ^(t)butyldiphenylsilyloxy or other suchsubstituted silyloxy protecting group allyl, methoxymethyl,methoxyethyl, and benzyloxymethyl;R_(S1) is selected from the group consisting of 4-methoxyphenyl;substituted benzyl groups; alkylacyl, arylacyl or alkylarylacyl, andsubstituted alkylacyl, arylacyl or alkylarylacyl protecting groups;carbonate protecting groups; a ^(t)butyldiphenylsilyloxy or other suchsubstituted silyloxy protecting group allyl, methoxymethyl,methoxyethyl, and benzyloxymethyl;or R_(S4) and R_(B) may be combined to form a cyclic carbamate;R_(P) (adjacent the O linking atom to the benzyl) is selected from thegroup consisting of 4-methoxyphenyl; benzyl, substituted benzyl groups;alkylacyl, arylacyl and alkylarylacyl, or substituted alkylacyl,arylacyl and alkylarylacyl protecting groups; and carbonate protectinggroups;R_(P) (adjacent the O linking atom to C) is selected from the groupconsisting of 4-methoxyphenyl; benzyl, substituted benzyl groups;alkylacyl, arylacyl and alkylarylacyl, or substituted alkylacyl,arylacyl and alkylarylacyl protecting groups; carbonate protectinggroups, silyl protecting groups, carbamate protecting groups, and C₃-C₅alkenyl; andA includes but is not limited to; H, methoxy, methyl; other suitablesubstituents will be known to those in the art.

In a fourteenth aspect the invention provides for a trisaccharidebuilding block for the preparation of synthetic heparinoids, saidbuilding block of General Formula XIV,

wherein, X₂ is defined as in General Formula II,R_(B) and R_(S1) are defined as in General Formula X,R_(S) is defined as in General Formula I,R_(P) is defined as in General Formula V,R_(E) is defined as in General Formula II,R_(B1) is defined as being selected from R_(B) of General Formula IV,with the addition that R_(B1) can combine together with R_(H2) to form acyclic carbamate,R_(H2) is defined as being selected from R_(H) of General Formula I,with the addition that R_(H2) can combine together with R_(B1) to form acyclic carbamate, andR_(H) is defined as in General Formula I orX₂ is selected from a hydroxyl group; thioalkyl, thioaryl, halogen,trichloroacetimidoyl, phosphate and related phosphate ester type leavinggroups, a ^(t)butyldiphenylsilyloxy or other such substituted silyloxyprotecting group; and the stereochemistry may be alpha or beta;R_(P) (adjacent block E) is selected from the group consisting of4-methoxyphenyl; benzyl, substituted benzyl groups; alkylacyl, arylacyland alkylarylacyl, or substituted alkylacyl, arylacyl and alkylarylacylprotecting groups; and carbonate protecting groups;R_(P) (adjacent Block C) is selected from the group consisting of4-methoxyphenyl; benzyl, substituted benzyl groups; alkylacyl, arylacyland alkylarylacyl, or substituted alkylacyl, arylacyl and alkylarylacylprotecting groups; carbonate protecting groups, silyl protecting groups,carbamate protecting groups, and C₃-C₅ alkenyl;R_(E) is selected from the group consisting of methyl, C₂-C₅ alkyl;substituted alkyl, C₃-C₅ alkenyl; or, benzyl and substituted benzylgroups;R_(B1) is selected from the group consisting of an azido function, anamine; an NH-Dde or NH-DTPM group, or R_(H2) and R_(B1) can combinetogether to form a cyclic carbamate;R_(H) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, and allyloxycarbonyl;R_(H2) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, and allyloxycarbonyl, or R_(H2) andR_(B1) independently can combine together to form a cyclic carbamate;R_(S) (on block E) is selected from the group consisting of4-methoxyphenyl; 4-methoxybenzyl, substituted benzyl groups; alkylacyl,benzoyl, arylacyl or alkylarylacyl, and substituted alkylacyl,4-chlorobenzoyl, arylacyl or alkylarylacyl protecting groups;allyloxycarbonyl, ethoxycarbonyl, tertbutoxycarbonyl, carbonateprotecting groups; or is selected from the group consisting of4-methoxyphenyl; substituted benzyl groups; alkylacyl, arylacyl oralkylarylacyl, and substituted alkylacyl, arylacyl or alkylarylacylprotecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup allyl, methoxymethyl, methoxyethyl, and benzyloxymethyl;or R_(S) and R_(H) can be combined to form a cyclic acetal or ketalmoiety;R_(S) (on block C and adjacent the ring O) is selected from the groupconsisting of 4-methoxyphenyl; substituted benzyl groups; alkylacyl,arylacyl or alkylarylacyl, and substituted alkylacyl, arylacyl oralkylarylacyl protecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup allyl, methoxymethyl, methoxyethyl, and benzyloxymethyl;R_(S) (on block C and adjacent the O linking atom) is selected from thegroup consisting of 4-methoxyphenyl; substituted benzyl groups;alkylacyl, arylacyl or alkylarylacyl, and substituted alkylacyl,arylacyl or alkylarylacyl protecting groups; carbonate protectinggroups; a ^(t)butyldiphenylsilyloxy or other such substituted silyloxyprotecting group allyl, methoxymethyl, methoxyethyl, andbenzyloxymethyl;or R_(S) and R_(B) may be combined to form a cyclic carbamate;R_(B) is selected from the group consisting of an azido function, anamine; an NH-Dde or NH-DTPM group, or R_(S4) and R_(B) can combinetogether to form a cyclic carbamate.

In a fifteenth aspect the invention provides for a trisaccharidebuilding block for the preparation of synthetic heparinoids, saidbuilding block of General Formula XV,

wherein, X₁ is defined as in General Formula IR_(A) and R_(H1) are defined as in General Formula VIII,R_(S) is defined as in General Formula I,R_(H) is defined as in General Formula I,R_(E) is defined as in General Formula II,R_(B) and R_(S1) are defined as in General Formula X, andR_(L) is defined as in General Formula I, orX₁ is selected from the group consisting of hydroxy, alkenyloxy, alkoxy,aryloxy, benzyloxy, substituted benzyloxy; thioalkyl, thioaryl, halogen,imidoyl, phosphate and related phosphate ester type leaving groups, a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; a lipoaminoacid or other such group suitable for conjugation todelivery systems or solid supports; and the stereochemistry may be alphaor beta;R_(H) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, and allyloxycarbonyl;R_(H1) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, and allyloxycarbonyl;R_(A) is selected from the group consisting of an azido function, anamine; an NH-Dde, NH-DTPM, NH-Fmoc, NH-Boc, NH-Cbz, NH-Troc,N-phthalimido, NH—Ac, NH-Allyloxycarbonyl; or R_(H) and R_(A) cancombine together to form a cyclic carbamate;R_(S) (on block A) is selected from the group consisting of4-methoxyphenyl; substituted benzyl groups; alkylacyl, arylacyl oralkylarylacyl, and substituted alkylacyl, arylacyl or alkylarylacylprotecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; allyl, methoxymethyl, methoxyethyl, and benzyloxymethyl;R_(S) (on block B) is selected from the group consisting of4-methoxyphenyl; substituted benzyl groups; alkylacyl, arylacyl oralkylarylacyl, and substituted alkylacyl, arylacyl or alkylarylacylprotecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; allyl, methoxymethyl, methoxyethyl, and benzyloxymethyl;R_(S) (on block C) is selected from the group consisting of4-methoxyphenyl; substituted benzyl groups; alkylacyl, arylacyl oralkylarylacyl, and substituted alkylacyl, arylacyl or alkylarylacylprotecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup allyl, methoxymethyl, methoxyethyl, and benzyloxymethyl;R_(S4) is selected from the group consisting of 4-methoxyphenyl;substituted benzyl groups; alkylacyl, arylacyl or alkylarylacyl, andsubstituted alkylacyl, arylacyl or alkylarylacyl protecting groups;carbonate protecting groups; a ^(t)butyldiphenylsilyloxy or other suchsubstituted silyloxy protecting group; allyl, methoxymethyl,methoxyethyl, and benzyloxymethyl,or R_(S4) and R_(B) may be combined to form a cyclic carbamate;R_(E) is selected from the group consisting of methyl, C₂-C₅ alkyl;substituted alkyl, C₃-C₅ alkenyl; or, benzyl and substituted benzylgroups;R_(B) is selected from the group consisting of an azido function, anamine; an NH-Dde or NH-DTPM group, or R_(S4) and R_(B) can combinetogether to form a cyclic carbamate;R_(L) is selected from an H atom; a levulinoyl, chloroacetyl,4-acetoxybenzoyl, 4-acetamidobenzoyl, 4-azidobenzoyl, or othersubstituted benzoyl type protecting group; a benzyl group, a4-acetoxybenzyl, 4-acetamidobenzyl or other such suitable substitutedbenzyl type protecting group; γ-aminobutyryl,4-N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-butyryl,4-N-[1-(1,3-dimethyl-2,4,6(1H,3H,5H)-trioxopyrimidin-5-ylidene)methylamino]-butyryl,4-N-Alloc-butyryl, 4-N-Fmoc-butyryl, 4-N-Boc-butyryl type protectinggroups; allyloxycarbonyl, allyl ether, and carbonate type protectinggroups.

In a sixteenth aspect the invention provides for a tetrasaccharidebuilding block for the preparation of synthetic heparinoids, saidbuilding block of General Formula XVI,

wherein, X₁ is defined as in General Formula IR_(A) and R_(H1) are defined as in General Formula VIII,R_(S) is defined as in General Formula I,R_(H) is defined as in General Formula I,R_(E) is defined as in General Formula II,R_(B) and R_(S1) are defined as in General Formula X,R_(P) is as defined in General Formula V, andR_(L) is as defined in General Formula I, orX₁ is selected from the group consisting of hydroxy, alkenyloxy, alkoxy,aryloxy, benzyloxy, substituted benzyloxy; thioalkyl, thioaryl, halogen,imidoyl, phosphate and related phosphate ester type leaving groups, a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; a lipoaminoacid or other such group suitable for conjugation todelivery systems or solid supports; and the stereochemistry may be alphaor beta,R_(H) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, and allyloxycarbonyl;R_(H1) is selected from the group consisting of benzyl or substitutedbenzyl protecting group, allyl, allyloxycarbonyl, or R_(H1) and R_(A)can combine together to form a cyclic carbamate;R_(A) is selected from the group consisting of an azido function, anamine; an NH-Dde, NH-DTPM, NH-Fmoc, NH-Boc, NH-Cbz, NH-Troc,N-phthalimido, NH—Ac, NH-Allyloxycarbonyl; or R_(H1) and R_(A) cancombine together to form a cyclic carbamate,R_(S) (on block A) is selected from the group consisting of4-methoxyphenyl; substituted benzyl groups; alkylacyl, arylacyl oralkylarylacyl, and substituted alkylacyl, arylacyl or alkylarylacylprotecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; allyl, methoxymethyl, methoxyethyl, and benzyloxymethyl;R_(S) (on block B) is selected from the group consisting of4-methoxyphenyl; substituted benzyl groups; alkylacyl, arylacyl oralkylarylacyl, and substituted alkylacyl, arylacyl or alkylarylacylprotecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; allyl, methoxymethyl, methoxyethyl, and benzyloxymethyl;R_(S) (on block C and adjacent the ring oxygen) is selected from thegroup consisting of 4-methoxyphenyl; substituted benzyl groups;alkylacyl, arylacyl or alkylarylacyl, and substituted alkylacyl,arylacyl or alkylarylacyl protecting groups; carbonate protectinggroups; a ^(t)butyldiphenylsilyloxy or other such substituted silyloxyprotecting group; allyl, methoxymethyl, and methoxyethyl,benzyloxymethyl;R_(S) (on block C and adjacent the linking O) is selected from the groupconsisting of 4-methoxyphenyl; substituted benzyl groups; alkylacyl,arylacyl or alkylarylacyl, and substituted alkylacyl, arylacyl oralkylarylacyl protecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; allyl, methoxymethyl, methoxyethyl, and benzyloxymethyl,or R_(S4) and R_(B) may be combined to form a cyclic carbamate,R_(E) (on block D) is selected from the group consisting of methyl,C₂-C₅ alkyl; substituted alkyl, C₃-C₅ alkenyl; or, benzyl andsubstituted benzyl groups;R_(E) (on block B) is selected from the group consisting of methyl,C₂-C₅ alkyl; substituted alkyl, C₃-C₅ alkenyl; or, benzyl andsubstituted benzyl groups;R_(B) is selected from the group consisting of an azido function, anamine; an NH-Dde or NH-DTPM group, or R_(S4) and R_(B) can combinetogether to form a cyclic carbamate;R_(P) (adjacent R_(L)) is selected from the group consisting of4-methoxyphenyl; benzyl, substituted benzyl groups; alkylacyl, arylacyland alkylarylacyl, or substituted alkylacyl, arylacyl and alkylarylacylprotecting groups; and carbonate protecting groups;R_(P) (on group D and adjacent group C) is selected from the groupconsisting of 4-methoxyphenyl; benzyl, substituted benzyl groups;alkylacyl, arylacyl and alkylarylacyl, or substituted alkylacyl,arylacyl and alkylarylacyl protecting groups; carbonate protectinggroups, silyl protecting groups, carbamate protecting groups, C₃-C₅alkenyl;R_(L) is selected from an H atom; a levulinoyl, chloroacetyl,4-acetoxybenzoyl, 4-acetamidobenzoyl, 4-azidobenzoyl, or othersubstituted benzoyl type protecting group; a benzyl group, a4-acetoxybenzyl, 4-acetamidobenzyl or other such suitable substitutedbenzyl type protecting group; γ-aminobutyryl,4-N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-butyryl,4-N-[1-(1,3-dimethyl-2,4,6(1H,3H,5H)-trioxopyrimidin-5-ylidene)methylamino]-butyryl,4-N-Alloc-butyryl, 4-N-Fmoc-butyryl, 4-N-Boc-butyryl type protectinggroups; allyloxycarbonyl, allyl ether, carbonate type protecting groups.

In an seventeenth aspect the invention provides for a tetrasaccharidebuilding block for the preparation of synthetic heparinoids, saidbuilding block of General Formula XVII,

wherein, X₂ is defined as in General Formula IV,R_(H) is defined as in General Formula I,R_(E) is defined as in General Formula II,R_(B) and R_(S1) are defined as in General Formula X,R_(S) is defined as in General Formula I,R_(P) is defined as in General Formula V,

-   -   R_(L) is defined as in General Formula I, and        R_(B1) and R_(H2) are defined as in General Formula XIV, or        R_(H) is selected from the group consisting of benzyl or        substituted benzyl protecting group, allyl, and        allyloxycarbonyl;        R_(H2) is selected from the group consisting of benzyl or        substituted benzyl protecting group, allyl, and        allyloxycarbonyl, or R_(H2) and R_(B1) independently can combine        together to form a cyclic carbamate;        R_(S) (on block B) is selected from the group consisting of        4-methoxyphenyl; substituted benzyl groups; alkylacyl, arylacyl        or alkylarylacyl, and substituted alkylacyl, arylacyl or        alkylarylacyl protecting groups; carbonate protecting groups; a        ^(t)butyldiphenylsilyloxy or other such substituted silyloxy        protecting group; allyl, methoxymethyl, methoxyethyl, and        benzyloxymethyl;        R_(S) (on block C and adjacent the ring O) is selected from the        group consisting of 4-methoxyphenyl; substituted benzyl groups;        alkylacyl, arylacyl or alkylarylacyl, and substituted alkylacyl,        arylacyl or alkylarylacyl protecting groups; carbonate        protecting groups; a ^(t)butyldiphenylsilyloxy or other such        substituted silyloxy protecting group; allyl, methoxymethyl,        methoxyethyl, and benzyloxymethyl;        R_(S) (on block C and adjacent the O linking atom) is selected        from the group consisting of 4-methoxyphenyl; substituted benzyl        groups; alkylacyl, arylacyl or alkylarylacyl, and substituted        alkylacyl, arylacyl or alkylarylacyl protecting groups;        carbonate protecting groups; a ^(t)butyldiphenylsilyloxy or        other such substituted silyloxy protecting group; allyl,        methoxymethyl, methoxyethyl, and benzyloxymethyl; or this R_(S)        and R_(B) may be combined to form a cyclic carbamate;        R_(S) (on block E) is selected from the group consisting of        4-methoxyphenyl; 4-methoxybenzyl, substituted benzyl groups;        alkylacyl, benzoyl, arylacyl or alkylarylacyl, and substituted        alkylacyl, 4-chlorobenzoyl, arylacyl or alkylarylacyl protecting        groups; allyloxycarbonyl, ethoxycarbonyl, tertbutoxycarbonyl,        carbonate protecting groups; or is selected from the group        consisting of 4-methoxyphenyl; substituted benzyl groups;        alkylacyl, arylacyl or alkylarylacyl, and substituted alkylacyl,        arylacyl or alkylarylacyl protecting groups; carbonate        protecting groups; a ^(t)butyldiphenylsilyloxy or other such        substituted silyloxy protecting group; allyl, methoxymethyl, and        methoxyethyl, benzyloxymethyl; or this R_(S) and R_(H) can be        combined to form a cyclic acetal or ketal moiety;        R_(E) (on block D) is selected from the group consisting of        methyl, C₂-C₅ alkyl; substituted alkyl, C₃-C₅ alkenyl; or,        benzyl and substituted benzyl groups;        R_(E) (on block B) is selected from the group consisting of        methyl, C₂-C₅ alkyl; substituted alkyl, C₃-C₅ alkenyl; or,        benzyl and substituted benzyl groups;        R_(B) is selected from the group consisting of an azido        function, an amine; an NH-Dde or NH-DTPM group, or R_(S4) and        R_(B) can combine together to form a cyclic carbamate;        R_(B1) is selected from the group consisting of an azido        function, an amine; an NH-Dde or NH-DTPM group, or R_(H2) and        R_(B1) can combine together to form a cyclic carbamate;        R_(P) (on block D adjacent block E) is selected from the group        consisting of 4-methoxyphenyl; benzyl, substituted benzyl        groups; alkylacyl, arylacyl and alkylarylacyl, or substituted        alkylacyl, arylacyl and alkylarylacyl protecting groups; and        carbonate protecting groups;        R_(P) (on block D adjacent block C) is selected from the group        consisting of 4-methoxyphenyl; benzyl, substituted benzyl        groups; alkylacyl, arylacyl and alkylarylacyl, or substituted        alkylacyl, arylacyl and alkylarylacyl protecting groups;        carbonate protecting groups, silyl protecting groups, carbamate        protecting groups, and C₃-C₅ alkenyl;        X₂ is selected from a hydroxyl group; thioalkyl, thioaryl,        halogen, trichloroacetimidoyl, phosphate and related phosphate        ester type leaving groups, a ^(t)butyldiphenylsilyloxy or other        such substituted silyloxy protecting group; and the        stereochemistry may be alpha or beta.

In an eighteenth aspect the invention provides for a pentasaccharidebuilding block for the preparation of synthetic heparinoids, saidbuilding block of General Formula XVIII,

wherein, X₁ is defined as in General Formula IR_(A) and R_(H1) are defined as in General Formula VIII, and R_(H1) canalso be allyl and alloxycarbonyl or R_(A) and R_(H1) can combinetogether to form a cyclic carbamate.R_(S) is defined as in General Formula I,R_(H) is defined as in General Formula I or R_(H) is selected from thegroup consisting of benzyl or substituted benzyl protecting group,allyl, and allyloxycarbonyl,R_(E) is defined as in General Formula II,R_(B) and R_(S1) are defined as in General Formula X,R_(P) is defined as in General Formula V, and may be benzyl,R_(P) (adjacent the link from D to C) may also be silyl protectinggroups, carbamate protecting groups, C₃-C₅ alkenyl, andR_(B1) and R_(H2) are defined as in General Formula XIV or R_(H2) isselected from the group consisting of benzyl or substituted benzylprotecting group, allyl, allyloxycarbonyl, or R_(H2) and R_(B1)independently can combine together to form a cyclic carbamate,R_(S1) on block C(R_(S4) in the claims) is selected from the groupconsisting of 4-methoxyphenyl; substituted benzyl groups; alkylacyl,arylacyl or alkylarylacyl, and substituted alkylacyl, arylacyl oralkylarylacyl protecting groups; carbonate protecting groups; a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; allyl, methoxymethyl, methoxyethyl, and benzyloxymethyl,or R_(S4) and R_(B) may be combined to form a cyclic carbamate;R_(S) on block E C B A, (R_(S1,2,3,5) in the claims) can be a^(t)butyldiphenylsilyloxy or other such substituted silyloxy protectinggroup; allyl, methoxymethyl, methoxyethyl, and benzyloxymethyl.

In a nineteenth aspect, the invention provides a method for thepreparation of compounds of the eighth aspect, involving the step ofreacting a compound of the second or third aspect with a compound of thefirst or seventh aspect to form a new glycosidic bond.

In a twentieth aspect, the invention provides a method for thepreparation of compounds of the eighth aspect, involving the step ofselectively removing the protecting group R_(M) from compounds of theninth aspect and oxidizing the product of said deprotection.

In a twenty first aspect, the invention provides a method for thepreparation of compounds of the tenth aspect, involving the step ofreacting a compound of the fifth aspect with a compound of the fourth orseventh aspect to form a new glycosidic bond.

In a twenty second aspect, the invention provides a method for thepreparation of compounds of the eleventh aspect, involving the step ofreacting a compound of the fifth aspect with a compound of the sixth orseventh aspect to form a new glycosidic bond.

In a twenty third aspect, the invention provides a method forpreparation of compounds of the thirteenth aspect involving the reactionof a compound of the fourth or seventh aspect with a suitable donormolecule, to form a new glycosidic bond.

In a twenty fourth aspect, the invention provides a method for thepreparation of compounds of the fourteenth aspect involving the step ofusing any one or more of the compounds of the fourth, fifth, sixth,seventh, tenth, eleventh, twelfth or thirteenth aspect in a glycosidicbond forming reaction.

In a twenty fifth aspect, the invention provides a method for thepreparation of compounds of the fifteenth aspect involving the step ofusing any one or more compounds of the first, second, third, fourth,seventh, eighth and ninth aspects in a glycosidic bond forming reaction.

In a twenty sixth aspect, the invention provides a method for thepreparation of compounds of the sixteenth aspect involving the step ofusing any one or more of the compounds of the first, second third,fourth, fifth, seventh, eighth, ninth, tenth, thirteenth or fifteenthaspect in a glycosidic bond forming reaction.

In a twenty seventh aspect, the invention provides a method for thepreparation of compounds of the seventeenth aspect involving the step ofusing any one or more of the compounds of the second, third, fourth,fifth, seventh, tenth, eleventh, twelfth, thirteenth or fourteenthaspect in a glycosidic bond forming reaction.

In a twenty eighth aspect, the invention provides a method for thepreparation of compounds of the eighteenth aspect involving the step ofusing any one or more of the compounds of the 1, 2, 3, 4, 5, 7, 8, 9,10, 11, 12, 13, 14, or 15, 16 or 17^(th) aspect in a glycosidic bondforming reaction.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a proton NMR spectrum of the Bis-methyl ester of compoundP-33.

FIG. 2 is a proton NMR spectrum of the compound P-40.

BEST MODE

Embodiments of the invention will be described with reference to thefollowing examples: Standard operating protocols (SOP's) are providedfor many of the examples.

LIST OF ABBREVIATIONS

AcO: Acetyl,

All: Allyl,

Alloc: Allyloxycarbonyl,

Bn: Benzyl,

Bz: Benzoyl,

CAN: (NH₄)₂Ce^(IV)(NO₃)₆, ceric ammonium (IV) nitrate,

ClAc: Monochloroacetyl,

Cres: p-Tolyl,

DCC: Dicyclohexylcarbodiimide,

Dde: 1-(4,4-dimethyl-2,6-dioxocyclohex-ylidene)ethyl,

DEAD: Diethyl azodicarboxylate,

DIPEA: Diisopropylethylamine,

DMAP: 4-N,N-dimethylaminopyridine,

DMF: N,N-Dimethylformamide,

DMTST: Dimethyl (methylthio)sulfoniumtetrafluoromethansulfonate,

DTPMB: 2,6-di-tert-butyl-4-methylpyridine

DTPM: (1,3-dimethyl-2,4,6 (1H, 3H, 5H)-trioxopyrimidin-5-ylidene)methyl,

Lev: 4-Oxopentanoyl,

MCPBA: 3-chloroperbenzoic acid,

Mes: Methanesulfonyl,

Mp: 4-Methoxyphenyl,

Mpm: 4-methoxybenzyl,

NBS: N-Bromosuccinimide,

NIS: N-Iodosuccinimide,

NMP: N-Methylpyrollidone

NPht: N-Phthaloyl

PDC: Pyridiniumdichromate,

Pent: n-Pentenyl,

Ph₃P: Triphenylphosphine,

Piv: Pivaloyl,

TBAF: Tetrabutylammoniumfluoride,

TBDMS: tert-Butyldimethylsilyl,

TBDPS: tert-Butyldiphenylsilyl,

TCA: Trichloroacetimidyl,

TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxyl,

TFA: Trifluoroacetic acid,

TFAA: Trifluoroacetic acid anhydride,

Tf: Trifluoromethanesulfonyl,

TfN₃: Trifluoromethanesulfonyl azide, prepared from NaN₃ and Tf₂O,

TfOH: Trifluoromethanesulfonic acid,

THF: Terahydrofuran,

TMS: Trimethylsilyl,

Tos: p-Toluenesulfonyl,

p-TosOH: p-Toluenesulfonic acid,

Trit: Triphenylmethyl.

Standard Operating Procedures

Standard Operating Procedure 1: Formation of Benzylidene acetals

Standard Operating Procedure 2: Formation of p-Methoxybenzylideneacetals

Standard Operating Procedure 3: Formation of isopropylidene acetals:

Standard Operating Procedure 4: Dealkylidenation (Removal ofisopropylidene, benzylidene and p-methoxybenzylidene)

Standard Operating Procedure 5: Regioselective opening of thep-methoxybenzyliden acetal to a 6-O-pMethoxybenzyl ether

Standard Operating Procedure 6: Regioselective opening of a benzylidenering to a 4-O-benzyl ether

Standard Operating Procedure 7: Introduction of a benzyl orp-methoxybenzyl ether

Standard Operating Procedure 8: Introduction of atert-butyldiphenylsilyl ether

Standard Operating Procedure 9: Cleavage of a tert-Butyl-diphenylsilylether

Standard Operating Procedure 10: Introduction of a N-DTPM-group

Standard Operating Procedure 11: Cleavage of a N-DTPM-group

Standard Operating Procedure 12: Introduction of an azide group viadiazo transfer reaction

Standard Operating Procedure 13: Hydrolysis of thioglycosides (NBS)

Standard Operating Procedure 14: Hydrolysis of thioglycosides (NIS)

Standard Operating Procedure 15: Chemoselective Oxidation to Uronicacids

Standard Operating Procedure 16: Methyl ester formation on the Uronicacids

Standard Operating Procedure 17: Regioselective 6-O-Benzoylation

Standard Operating Procedure 18: Common procedure for O-Benzoylation

Standard Operating Procedure 19: Common procedure for O-Acetylation

Standard Operating Procedure 20: PDC-oxidation of alcohols to carboxylicacids

Standard Operating Procedure 21: Chemoselective 1-O-Benzoyl cleavage

Standard Operating Procedure 22: Deacylation under Zemplen conditions

Standard Operating Procedure 23: Introduction of the 4-Oxopentanoyl(=Levulinoyl) group

Standard Operating Procedure 24: Cleavage of the 4-Oxopentanoyl(=Levulinoyl) group

Standard Operating Procedure 25: Formation of Trichloroacetimidates

Standard Operating Procedure 26: Regioselective introduction of a6-O-pMethoxyphenyl group under Mitsunobu conditions

Standard Operating Procedure 27: Cleavage of the p-Methoxyphenyl ether

Standard Operating Procedure 28: Cleavage of p-Methoxybenzyl ethers

Standard Operating Procedure 29: Formation of a 2,3-cyclic carbamate

Standard Operating Procedure 30: Cleavage of the N-phthaloyl group

Standard Operating Procedure 31: Introduction of a thiocresyl ether atthe reducing end

Standard Operating Procedure 32: Glycosylation with thioglycosidesNIS-promoted glycosylation

DMTST promoted glycosylations:

Standard Operating Procedure 33: Glycosylations withtrichloroacetimidates

Standard Operating Procedure 34: Glycosylations using 2,3-cyclocarbamoylprotected pThiocresyl glycosides as glycosyl donors

Standard Operating Procedure 35: Introduction of an Alloc-group

Standard Operating Procedure 36: Cleavage of an Alloc-group

Standard Operating Procedure 37: Lewis acid mediated benzylation

Standard Operating Procedure 38: benzylation under mild basic conditions

Standard Operating Procedure 39: Ester cleavage under very mildconditions

Standard Operating Procedure 1: Formation of Benzylidene Acetals

The starting material (47.5 mmol) was dissolved in acetonitrile (100-200mL) and reacted with benzaldehyde dimethyl acetal (1.2 equiv.) and acatalytic amount of p-toluenesulphonic acid monohydrate (0.01-0.1equiv). The reaction was stirred at 50° C. under reduced pressure (350mbar) until the TLC shows completion. Subsequently, the mixture wasneutralized with triethylamine (pH=9) and concentrated in vacuo. Theremaining residue was dissolved in an organic solvent (e.g.dichloromethane or ethyl acetate) and extracted with H₂O, saturatedbrine solution, dried over Na₂SO₄ and concentrated. Final purificationwas achieved either by crystallization or by silica gel chromatography.The typical yields for the product formation varied between 70 and 95%.

Standard Operating Procedure 2: Formation of p-MethoxybenzylideneAcetals

The starting material (47.5 mmol) was dissolved in DMF/acetonitrile(1/1, 100-200 mL) and reacted with p-methoxybenzaldehyde dimethyl acetal(1.2 equiv.) and a catalytic amount of p-toluenesulphonic acidmonohydrate (0.01-0.1 equiv). The reaction was stirred between 50-60° C.under reduced pressure (350 mbar) until the TLC shows completion.Subsequently, the mixture was neutralized with triethylamine (pH≈9) andconcentrated in vacuo. The remaining residue was dissolved in an organicsolvent (e.g. dichloromethane or ethyl acetate) and extracted with H₂O,saturated brine solution, dried over Na₂SO₄ and concentrated. Finalpurification was achieved either by crystallization or by silica gelchromatography. The typical yields for the product formation variedbetween 70 and 85%.

Standard Operating Procedure 3: Formation of Isopropylidene Acetals:

A solution of starting material (10 mmol) and catalytic amounts ofcamphorsulfonic acid (0.01-0.1 equiv) in 2,2-dimethoxypropane (50 mL)was stirred at 25° C. until completion, neutralized with triethylamineand concentrated. The remaining residue was dissolved in an organicsolvent (e.g., dichloromethane or ethyl acetate) and extracted with H₂Oand saturated brine solution. The organic layer was dried over Na₂SO₄and concentrated. Final purification was achieved either bycrystallization or by silica gel chromatography. The typical yields forthe product formation varied between 75 and 93%.

Standard Operating Procedure 4: Dealkylidenation (Removal ofisopropylidene, benzylidene and p-methoxybenzylidene)

A solution of the acetal (31 mmol) in 150 mL dichloromethane was cooledto 0° C. and reacted with 80% aqueous TFA (20.0 mL, cooled to 0° C.).After stirring at 0° C. until completion, the reaction mixture wasneutralized with 30% NaOH solution and extracted with water andsaturated brine solution. The organic layer was dried over Na₂SO₄ andconcentrated. Final purification was achieved either by crystallizationor by silica gel chromatography. The typical yields for the productformation varied between 70 and 95%.

Modification Using p-TosOHxOH₂ in MeOH/CH₃CN for Cleavage:

The acetal (16.6 mmol) was dissolved in 100 mL of dry acetonitrile and25 mL MeOH and the solution was reacted with catalytic amounts ofp-TosOHxOH₂. The reaction mixture was heated at elevated Temperature(between 40 and 60° C.) until completion and then neutralized with Et₃N,concentrated in vacuo and purified either by crystallization or bysilica gel chromatography. The typical yields for the product formationvaried between 70 and 95%.

Standard Operating Procedure 5: Regioselective Opening of thep-Methoxybenzyliden Acetal to a 6-O-pMethoxybenzyl Ether

A suspension of the starting sugar (10.2 mmol), molecular sieves 3 Å(6.5 g, freshly activated) and Na(CN)BH₃ (3.85 g, 58.2 mmol) in dry DMF(90 mL) was stirred for 1 hr at r.t. and cooled down to 0° C.Subsequently, a solution of TFA (11.2 mL, 143.9 mmol in 51 mL dry DMF)was added dropwise and stirring continued at 50 to 60° C. untilcompletion of the reaction. The reaction mixture was cooled to 20° C.,diluted with ethyl acetate and extracted with a saturated aqueous NaHCO₃solution and filtered through a celite pad. The combined organic layerswere washed with saturated brine solution, dried over MgSO₄ andconcentrated. Final purification was achieved either by crystallizationor by silica gel chromatography. The typical yields for the productformation varied between 70 and 90%.

Standard Operating Procedure 6: Regioselective Opening of a BenzylideneRing to a 4-O-benzyl Ether

A solution of the starting material (3.4 mmol) in 25 mL dichloromethaneis cooled to 0° C. and to it is added of a solution of BH₃ in THF (1 M,34 mL) and a solution of Bu₂BOTf in dichloromethane (1 M, 3.7 mL). Thereaction is stirred at 0° C. till completion and then quenched with 10mL Et₃N and 10 mL MeOH, concentrated and coevaporated three times withtoluene. Final purification was achieved either by crystallization or bysilica gel chromatography. The typical yield for the product formationvaried between 75 and 90%.

Standard Operating Procedure 7: Introduction of a Benzyl orp-methoxybenzyl Ether

The starting material (40.2 mmol) was dissolved in dryN,N′-dimethylformamide (100 mL) at 0° C. and reacted with NaH (48.24mmol, 1.2 eq per OH to be benzylated). Then benzyl bromide (1.1 eq perOH to be benzylated) was added dropwise and stirring continued at 0° C.until completion. The same conditions were applied for the introductionof an allyl ether (Allylbromide served as allylating reagent).

The excess of NaH was neutralized by careful addition of acetic acid,followed by concentration of the reaction mixture in vacuo. The residuewas dissolved in ethyl acetate and subsequently washed with water, 10%aqueous HCl solution, saturated aqueous NaHCO₃ solution, saturated brinesolution, dried over Na₂SO₄ and concentrated in vacuo. Finalpurification was achieved either by crystallization or by silica gelchromatography. The typical yield for the product formation variedbetween 70 and 92%.

The same procedure was followed for the formation of the p-methoxybenzylether except that p-methoxybenzyl chloride was added to the reactioninstead of benzyl bromide and the reaction was performed between 50 and60° C.

Standard Operating Procedure 8: Introduction of atert-butyldiphenylsilyl Ether

A mixture of the starting material (29.0 mmol) and imidazole (70.1 mmol)was dissolved in 80 mL anhydrous DMF and heated to 55° C. To thesolution was added tert-butyldiphenylchlorosilane (8.30 mL, 31.9 mmol)and stirring continued at 55° C. until completion. The reaction mixturewas then cooled to 20° C. and quenched with aqueous NaHCO₃ solution.After concentration in vacuo, the residue was taken up in ethyl acetateand the organic phase washed successively with water, 10% aqueous citricacid, water, saturated brine solution, dried over Na₂SO₄ and evaporated.Final purification was achieved either by crystallization or by silicagel chromatography. The typical yields for the product formation variedbetween 85 and 95%.

Standard Operating Procedure 9: Cleavage of a tert-Butyl-diphenylsilylEther

To a solution of the silyl ether (2.15 mmol) in 2.5 mL dry THF andacetic acid (3.44 mmol) was added 1 M TBAF solution in THF (3.22 mL) andstirring continued till completion of the reaction. Subsequently, thereaction mixture was concentrated in vacuo. Final purification wasachieved either by crystallization or by silica gel chromatography. Thetypical yields for the product formation varied between 85 and 97%.

Standard Operating Procedure 10: Introduction of a N-DTPM-Group

To a solution of the starting amine (24.5 mmol) in methanol (60 mL) isadded a solution of the DTPM reagent (5.43 g, 25.7 mmol) in methanol (60mL) at 60° C. After completion of the reaction, the reaction mixture wasconcentrated in vacuo, taken up in dichloromethane, extracted with waterand saturated brine solution, dried over MgSO₄ and evaporated. Finalpurification was achieved either by crystallization or by silica gelchromatography. The typical yields for the product formation variedbetween 85 and 97%.

Standard Operating Procedure 11: Cleavage of a N-DTPM-Group

The starting material (40.94 mmol) was dissolved in dry DMF (50 mL) andreacted with ethylene diamine (20 mL) at room temperature untilcompletion. The reaction mixture was concentrated in vacuo andcoevaporated with toluene. The residue was suspended in CHCl₃ andfiltered through a Celite pad. The filtrate was evaporated and finalpurification of the residue was achieved either by crystallization or bysilica gel chromatography. The typical yields for the product formationvaried between 85 and 92%.

Standard Operating Procedure 12: Introduction of an Azide Group ViaDiazo Transfer Reaction

a) Preparation of a trifluoromethansulfonylazide Solution:

A solution of sodium azide (492 mmol) in water (80 mL) was preparedunder N₂-atmosphere. To this stirred solution was added dichloro-methane(100 mL) at 0° C., followed by the addition of triflic anhydride (16.5mL) over 10 min. The mixture was further stirred for 2 hours at 0° C.,the organic layer was separated and the aqueous layer was extracted withdichloromethane (2×40 mL). The combined organic layers were washed withsaturated, aqueous NaHCO₃ solution (80 mL), water (80 mL) and dried overNa₂SO₄. After filtration, this solution was directly used for thediazotransfer reaction.

b) Diazotransfer Reaction:

To a solution of the starting material (26.0 mmol) and4-N,N′-(dimethylamino)pyridine (14.5 g) in acetonitrile (100 mL) wasadded dropwise TfN₃-solution (85 mL) at room temperature within 10 min.The reaction was stirred till complete conversion of the startingmaterial into the product. The reaction mixture was concentrated invacuo to 30 mL and suspended in chloroform. After filtration through aCelite pad, the filtrate was concentrated and the residue was purifiedby filtration through a short silica gel pad. The typical yields for theproduct formation varied between 85 and 95%.

Standard Operating Procedure 13: Hydrolysis of Thioglycosides (NBS)

The starting thioglycoside (33.4 mmol) was suspended in 240 mL Acetoneand 18 mL of distilled water and stirred for 45 min at −20° C. Afteraddition of NBS (155 mmol) stirring was continued at −20° C. Aftercompletion, the reaction was stopped by addition of NaS₂O₃/NaHCO₃ (20%aqueous solution, 1/1) and the mixture diluted with ethyl acetate,subsequently washed with water and saturated brine solution. The organiclayer was dried over Na₂SO₄ and concentrated in vacuo. Finalpurification was achieved either by crystallization or by silica gelchromatography. The typical yields for the product formation variedbetween 75 and 90%.

Standard Operating Procedure 14: Hydrolysis of Thioglycosides (NIS)

The starting thioglycoside (33.4 mmol) was suspended in 240 mL Acetoneand 18 mL of distilled water and stirred for 45 min at −20° C. Afteraddition of NIS (56.8 mmol) and TMSOTf (2.84 mmol) stirring wascontinued until completion. The reaction was stopped by addition ofNaS₂O₃/NaHCO₃ (20% aqueous solution, 1/1), diluted with ethyl acetateand washed with water and saturated brine solution. The organic layerwas dried over Na₂SO₄ and concentrated in vacuo. Final purification wasachieved either by crystallization (e.g. petroleum spirit/ethylacetate)or by silica gel chromatography. The typical yields for the productformation varied between 79 and 92%.

Standard Operating Procedure 15: Chemoselective Oxidation to UronicAcids

A solution of the starting material (20.0 mmol) in dichloromethane (141mL) was cooled to 0° C. and subsequently mixed with TEMPO (0.205 mmol in12.8 mL dichloromethane), Aliquat 336(N-methyl-N,N-dioctyl-1-octanaminium chloride) (12.8 mL of a 0.08 Msolution in dichloromethane) and KBr (2.08 mmol in 4.17 mL H₂O) andstirring continued at 0° C. After 5 mins, a suspension of Ca(OCl)₂ (43.6mmol) and NaHCO₃ (43.6 mmol) in 135 mL H₂O was added within 15 mins tothe reaction mixture and stirring at 0° C. was continued tillcompletion. The reaction was concentrated in vacuo and freeze dried. Thecrude residue was used as such for the next reactions.

Standard Operating Procedure 16: Methyl Ester Formation on the UronicAcids

The crude residue of the oxidation to the uronic acid was dissolved in50 mL Toluene and 50 mL Methanol and titurated with TMSCHN₂-solution (2Min hexane) until completion. The reaction mixture was quenched withacetic acid to destroy excess of esterification reagent and evaporatedin vacuo. Final purification was achieved by silica gel chromatography.The typical yields for the product formation varied between 65 and 80%over the steps oxidation and esterification.

Standard Operating Procedure 17: Regioselective 6-O-Benzoylation

The starting material (32.04 mmol) was dissolved in dry dichloromethane(50 mL) and dry pyridine (10 mL) and cooled down to −45° C. Benzoylchloride (32.04 mmol) was added dropwise and stirring continued at −45°C. until completion. The reaction was concentrated in vacuo andcoevaporated with toluene three times. The remaining residue wasdissolved in dichloromethane and washed with 10% aqueous citric acidsolution, saturated aqueous NaHCO₃ solution and saturated brinesolution, dried over Na₂SO₄ and evaporated in vacuo. Final purificationwas achieved either by crystallization or by silica gel chromatography.The typical yields for the product formation varied between 75 and 94%.

Standard Operating Procedure 18: Common Procedure for O-Benzoylation

To a solution of the starting material (11.9 mmol) and DMAP (13.6 mmol)in 1,2-dichloroethane was added dropwise benzoylchloride (1.7 g, 12.1mmol). at 0° C. The mixture was then left to stir until completion(dependent on the substrate between 20 to 55° C.). Subsequently, thereaction mixture was diluted with dichloromethane and washed with water,5% NaHSO₄ solution, saturated aqueous NaHCO₃ solution and saturatedbrine solution. The organic layer was dried over MgSO₄ followed byremoval of the solvent in vacuo to give a crude residue. Finalpurification was achieved either by crystallization or by silica gelchromatography. The typical yields for the product formation variedbetween 80 and 96%.

Standard Operating Procedure 19: Common Procedure for O-Acetylation

To a suspension of the starting material (235 mmol, 3 acetylation sites)in pyridine (350 mL) at 0° C. was added dropwise acetic anhydride (175mL). After completion of the addition, the reaction was allowed toreturn to room temperature and stirred until completion. The reactionmixture was evaporated to dryness and 3× coevaporated with toluene. Theresidue was taken up in dichloromethane and washed with 5% aqueousNaHSO₄-solution, saturated aqueous NaHCO₃-solution, water and saturatedbrine solution. The organic layer was dried over MgSO₄ and evaporated.Final purification of the residue was achieved either by crystallizationor by silica gel chromatography. The typical yields for the productformation varied between 88 and 98%.

Standard Operating Procedure 20: PDC-Oxidation of Alcohols to CarboxylicAcids

The starting material (1.15 mol) was dissolved in anhydrous DMF (7.0 mL)and reacted with PDC (11.5 mmol) under stirring at room temperatureuntil complete conversion into the uronic acid. The reaction mixture wassubsequently poured into 50 mL water and the whole extracted withdiethyl ether. The combined ether layers were washed with 10% aqueouscitric acid solution, filtered through a short silica gel pad, driedover MgSO₄, evaporated and dried under high vacuum.

Standard Operating Procedure 21: Chemoselective 1-O-Benzoyl Cleavage

The starting material (36.8 mmol) was dissolved in dry DMF (80 mL) andcooled to 0° C. Subsequently, hydrazine acetate (44.06 mmol) was addedand stirring continued until completion. After addition of acetone andacetic acid the reaction mixture was concentrated in vacuo. The residuewas dissolved in dichloromethane and extracted with 10% aqueous citricacid solution, saturated NaHCO₃ solution, water and saturated brinesolution, dried over MgSO₄, evaporated and dried under high vacuum.Final purification was achieved either by crystallization or by silicagel chromatography. The typical yields for the product formation variedbetween 72 and 88%.

Standard Operating Procedure 22: Deacylation Under Zemplen Conditions

The starting material (23.7 mmol) was suspended in dry MeOH (70 mL) andstirred for 30 mins at 0° C. Subsequently, NaOMe (0.1 equiv./0-Acylgroup) was added (positive flush of N₂) and stirring was continued at 0°C. until completion. Finally, the reaction was neutralized with 10%aqueous HCl and the solvent evaporated. Final purification was achievedeither by crystallization or by silica gel chromatography. The typicalyield for the product formation varied between 90 and 98%.

Standard Operating Procedure 23: Introduction of the 4-Oxopentanoyl(=Levulinoyl) Group

Preparation of the Lev₂O Solution:

To a solution of DCC (31.2 mmol) in 100 mL dichloromethane was addedlevulinic acid (62.4 mmol) and DIPEA (62.42 mmol). The supernatant wasused as such for the levulination reaction.

Reaction

The above Lev₂O solution was added to a solution of the starting sugar(15.6 mmol) dissolved in 25 mL of dry dichloromethane and stirring wascontinued until completion. Subsequently, the reaction mixture wasfiltered through a Celite pad and all combined organic layers wereextracted with 10% aqueous citric acid solution, saturated aqueous brinesolution, dried with Na₂SO₄ and concentrated. Final purification wasachieved either by crystallization or by silica gel chromatography. Thetypical yields for the product formation varied between 85 and 96%.

Standard Operating Procedure 24: Cleavage of the 4-Oxopentanoyl(=Levulinoyl) Group

A solution of the starting sugar (1.28 mmol) and acetic acid (1.35 mL)in pyridine (5.0 mL) was cooled to 0° C. followed by addition ofhydrazine hydrate (200 μL). Stirring at 0° C. was continued untilcompletion and the reaction mixture diluted with dichloromethane,subsequently extracted with 10% aqueous citric acid, 10% aqueous NaHCO₃solution, saturated brine solution, dried over Na₂SO₄, filtered andconcentrated. Final purification was achieved either by crystallizationor silica gel chromatography. The typical yields for the productformation varied between 80 and 95%.

Standard Operating Procedure 25: Formation of Trichloroacetimidates

a) with DBU:

A solution of the starting sugar (1.99 mmol) and trichloro-acetonitrile(601 μL, 5.87 mmol) in 5 mL dry dichloromethane was stirred at roomtemperature for 30 min. The reaction mixture was then cooled to 0° C.and DBU (100 μmol) added. Stirring was continued until completion(dependent on the substrate, stirring was performed from 0° C. to 20°C.). The reaction mixture was concentrated to one half of its volume anddirectly loaded on a short plug of silica gel and purified via silicagel chromatography. The typical yields for the product formation variedbetween 78 and 95%.

b) with K₂CO₃:

A solution of the starting sugar (1.99 mmol) and trichloro-acetonitrile(601 μL, 5.87 mmol) in 5 mL dry dichloromethane is stirred at r.t. for30 min. The reaction mixture was then cooled down to 0° C. and anhydrousK₂CO₃ (19.9 mmol) added. The reaction was stirred at 0° C. tillcompletion and then filtered through a celite pad. The filtrate wasdried over Na₂SO₄ and evaporated. Final purification was achieved eitherby crystallization or by silica gel chromatography. The typical yieldfor the product formation varied between 78 and 95%.

Standard Operating Procedure 26: Regioselective Introduction of a6-O-p-Methoxyphenyl Group Under Mitsunobu Conditions

A solution of the starting sugar (13.52 mmol), 4-methoxyphenol (20.3mmol) and triphenylphosphine (20.3 mmol) in 85 mL dry dichloromethanewas stirred at 0° C. for 45 min. After addition of DEAD-reagent (22.9mmol) at 0° C., the reaction mixture was further stirred at roomtemperature until completion, filtered through a celite pad, dilutedwith dichloromethane and extracted with 10% aqueous NaHCO₃/NaOH solution(1/1), 10% aqueous citric acid solution and aqueous saturated brinesolution. The organic layer was dried over Na₂SO₄ and concentrated.Final purification was achieved by silica gel chromatography. Thetypical yield for the product formation varied between 70 and 89%.

Standard Operating Procedure 27: Cleavage of the p-Methoxyphenyl Ether

The starting material (1.18 mmol) was dissolved in 30 mL acetonitrileand 7.5 mL water and cooled to 0° C. Subsequently, CAN (3.83 mmol) wasadded and stirring continued at 0° C. until completion. The reactionmixture was diluted with ethyl acetate and extracted with water. Theaqueous layer was made alkaline by addition of solid NaHCO₃ and backextracted with ethyl acetate. The combined organic layers were extractedwith saturated aqueous NaHCO₃ solution and saturated brine solution,dried over MgSO₄ and evaporated. Final purification was achieved bysilica gel chromatography. The typical yields for the product formationvaried between 73 and 89%.

Standard Operating Procedure 28: Cleavage of p-Methoxybenzyl Ethers

The starting material (0.60 mmol) was dissolved in 27 mL acetonitrileand 3.0 mL water and cooled to 0° C. Subsequently, CAN (4.5 equiv.) wasadded and stirring continued from 0° C. to room temperature untilcompletion. The reaction mixture was diluted with ethyl acetate andextracted with water. The aqueous layer was made alkaline by addition ofsolid NaHCO₃ and back extracted with ethyl acetate. The combined organiclayers were extracted with saturated aqueous NaHCO₃ solution andsaturated brine solution, dried over MgSO₄ and evaporated. Finalpurification was achieved by silica gel chromatography. The typicalyields for the product formation varied between 73 and 85%.

Standard Operating Procedure 29: Formation of a 2,3-cyclic Carbamate

To a stirred solution of the starting material (3.56 mmol) indichloromethane (100 mL) and 10% aqueous solution of NaHCO₃ (75 mL) wasadded a solution of triphosgene (1.25 mmol) in 10 mL drydichloromethane. The reaction was stirred at room temperature tillcompletion. The organic phase was washed with water, dried over Na₂SO₄,filtered and concentrated. Final purification was achieved either bycrystallization or silica gel chromatography. The typical yield for theproduct formation varied between 75 and 95%.

Standard Operating Procedure 30: Cleavage of the N-phthaloyl Group

The N-phthaloylated starting material (45.9 mmol) was dissolved inn-butanol (200 mL) and treated with 1,2-diaminoethane (50 mL) at 100° C.After stirring at 100° C. until completion, the reaction mixture wasconcentrated in vacuo, coevaporated with toluene three times and driedunder high vacuum. Final purification was achieved by silica gelchromatography. The typical yield for the product formation variedbetween 78 and 92%.

Standard Operating Procedure 31: Introduction of a Thiocresyl Ether atthe Reducing End

A solution of the 1-O-glycosyl acetate (10.48 mmol) and p-thiocresol(12.58 mmol) in dry dichloromethane (30 mL) was stirred at 0° C. andsubsequently activated by the addition of boron trifluoride diethylethercomplex (12.58 mmol) over 5 min. Stirring was continued (0° C.→20° C.)until completion and the reaction stopped by the addition of triethylamine (14.0 mmol). The reaction mixture was diluted with dichloromethaneand extracted with saturated NaHCO₃-solution, water and saturated brinesolution, dried over MgSO₄ and evaporated in vacuo. Final purificationwas achieved by crystallization or silica gel chromatography. Thetypical yield for the product formation varied between 81 and 92%.

Standard Operating Procedure 32: Glycosylation with Thioglycosides

a) NIS-Promoted Glycosylation

A mixture of glycosyl acceptor (1 mmol), thioglycoside (1 mmol) and 1.0g of freshly activated molecular sieves in 20 mL of a dry solvent (e.g.CH₃CN, CH₂Cl₂, Toluene, Ether) was stirred for 45 min at r.t and cooleddown to the reaction temperature. Subsequently, N-Iodosuccinimide (1.7mmol) was added and stirring continued for 20 min at the reactiontemperature. After the addition of a Lewis acid as promoter (e.g. TfOH,85-170 μmol), stirring was continued at the reaction temperature untilcompletion. The reaction mixture was quenched with triethyl amine,filtered through a celite pad and extracted with a 10% aqueousKHCO₃/Na₂S₂O₃ solution, water and saturated brine solution, dried overMgSO₄ and evaporated. Final purification was achieved by silica gelcolumn chromatography. The typical yields for the product formationvaried between 65 and 85%.

b) DMTST Promoted Glycosylations:

A mixture of glycosyl acceptor (1 mmol), thioglycoside (1 mmol) and 1.0g of freshly activated molecular sieves in 20 mL of a dry solvent (e.g.,CH₃CN, CH₂Cl₂, Toluene, Ether) was stirred for 45 min at r.t. and cooleddown to the reaction temperature. Subsequently, DMTST (3-5 equiv.) wasadded and stirring continued at the reaction temperature untilcompletion. The reaction mixture was quenched with triethyl amine,filtered through a celite pad and extracted with aqueousNaHCO₃-solution, water and saturated brine solution, dried over Na₂SO₄,concentrated in vacuo and purified by silica gel column chromatography.The typical yields for the product formation varied between 50 and 85%.

Standard Operating Procedure 33:

Glycosylations with Trichloroacetimidates

A suspension of the trichloroacetimidate (1.54 mmol), glycosyl acceptor(1.13 mmol) and freshly activated molecular sieves (1.0 g) in ananhydrous solvent (e.g., CH₃CN, CH₂Cl₂, Toluene, Ether, 20 mL) wasstirred at r.t. for 1 h and then cooled to reaction temperature.Subsequently, a catalytic amount of a promoter (e.g., TMSOTf, 0.01-0.1equiv.) was added and stirring continued at reaction temperature untilcompletion. The reaction was quenched with triethylamine) and filteredthrough a Celite pad. The combined organic layers were washed withaqueous NaHCO₃-solution and saturated brine solution, dried over Na₂SO₄,concentrated in vacuo and purified by silica gel column chromatography.The typical yields for the product formation varied between 50 and 85%.

Standard Operating Procedure 34: Glycosylations Using 2,3-cyclocarbamoylProtected pThiocresyl Glycosides as Glycosyl Donors

PhSCl (0.2 mmol, 2 equiv.) in dry dichloromethane (1 mL) was addeddropwise to a mixture of AgOTf (0.2 mmol) in dry dichloromethane (2 mL)at −78° C. containing freshly activated molecular sieves 3 Å. Afterstirring for 15 mins at −78° C., a solution of the thioglycoside (0.1mmol, 1 equiv.) and DTBMP (0.2 mmol, 2 equiv.) in dry dichloromethane (2mL) was slowly added. After further stirring for 15 mins at −78° C., theglycosyl acceptor (0.2 mmol, 2 equiv.) in dry dichloromethane (1 mL) wasslowly added and stirring continued until completion. The reaction wasquenched with saturated aqueous NaHCO₃ solution (1 mL), warmed to r.t.and diluted with dichloromethane. The organic layer was dried overMgSO₄, filtered and evaporated. Final purification was achieved bysilica gel chromatography. The typical yields for the product formationvaried between 60 and 90%.

Standard Operating Procedure 35: Introduction of an Alloc-Group

A solution of starting material (2 mmol), dry pyridine (5 mmol) and dryTHF (5 mL) was cooled to 0° C. Subsequently, Allylchloroformate (2.2mmol) were added dropwise and stirring was continued until completion.The reaction mixture was diluted with dichloromethane and subsequentlywashed with 10% aqueous citric acid solution, saturated NaHCO₃ solution,water and saturated brine solution. The organic layer was dried overNa₂SO₄, filtered and evaporated. Final purification was achieved eitherby crystallization or by silica gel chromatography. The typical yieldsfor the product formation varied between 80 and 95%.

Standard Operating Procedure 36: Cleavage of an Alloc-Group

A mixture of the Allyloxycarbonate (1.17 mmol), dimedone (1.33 mmol) andPd(Ph₃P)₄ (0.30 mmol) was dissolved in dry THF (60 mL) and stirred underAr atmosphere until completion of the reaction. The reaction mixture wasconcentrated in vacuo and purified by silica gel chromatography. Thetypical yields for the product formation varied between 78 and 97%.

Standard Operating Procedure 37: Lewis Acid Mediated Benzylation

To a stirred mixture of the starting material (1 mmol) and benzyltrichloroacetimidate in dry hexane/dichloromethane (10 mL, 2/1) wasadded Lewis acid (0.01-0.05 equiv., e.g. TMSOTf, TfOH) and stirring wascontinued at r.t. until completion. The reaction was quenched withtriethyl amine and concentrated. Final purification was achieved bysilica gel chromatography. The typical yields for the product formationvaried between 50 and 92%.

Standard Operating Procedure 38: Benzylation Under Mild Basic Conditions

The starting material (3.49 mmol) was dissolved in dry DMSO (20 mL) andcooled to 0° C. To the stirred solution were added successively benzylbromide (3.5 equiv./OH-group), barium oxide (1.5 equiv/OH-group),catalytic amounts of TBAI (0.05 eqiv./OH-group) and potassium hydroxide(3.5 equiv./OH-group). Stirring was continued from 0° C. to r.t. untilcompletion. The reaction was quenched with methanol, and further stirredfor 30 min. After dilution with ether, the organic layer was washed withwater and brine solution, dried over MgSO₄ and concentrated in vacuo.Final purification was achieved by silica gel chromatography.

Standard Operating Procedure 39: Ester Cleavage Under Aqueous Conditions

The starting material (0.3 mmol ester groups) was dissolved in 11.8 mLof a mixture of water and THF (3:7), cooled to 0° C. and reacted with 1M aqueous NaOH-solution (5.0 mL). Stirring was continued untilcompletion and the reaction mixture titurated with 10% aqueousHCl-solution to a pH of 9.5. After evaporation of the THF, the mixturewas freeze dried and the remaining residue purified by silica gelchromatography to yield the product. The typical yields for the productformation varied between 85 and 95%.

Example 1 Synthesis of Building Blocks A-1 and A-2 from N-AcetylGlucosamine

Example 1: Synthesis of building blocks A-1 and A-2 from N-Acetylglucosamine, yields are reported for R═H, conditions; a) Amberlite IR120 (ion exchange resin) (H⁺), MeOH, 60° C., (70%); b) 1 M NaOH, 120°C.; c) 1. SOP 10; 2. Ac₂O, pyridine; 3. NaOMe, MeOH (70%, 4 steps); d)SOP 1 (91% for R═H) or SOP 2 for R=Ome; e) SOP 11, (95%); f) SOP 12,(85%, 2 steps); g) SOP 7, (91%); h) SOP 4, (91%); i) SOP 17, (82%); j)SOP 5.

Preparation of A-1-i:

N-Acetyl-2-deoxy-α/β-D-glucopyranoside (8.5 g, 38.4 mmol) was suspendedin 100 mL dry methanol. Subsequently, 12.0 g Amberlite IR 120 ironexchange resin (H⁺-form) was added and the reaction mixture refluxed for70 hrs at 65° C. After cooling to 25° C., the iron exchange resin wasremoved by filtration and several times extracted with methanol. Thecombined methanol layers were neutralized with triethyl amine andconcentrated in vacuo. The crude residue was purified by crystallizationto furnish the title compound in 70% yield (α/β-mixture).

Preparation of A-1-iii:

Methyl glycoside A-1-I (20.6 mmol) was suspended in 100 mL aqueous NaOHsolution (1 M) and stirred under reflux at 120° C. until completion.After cooling and neutralization with 10% aqueous HCl, the mixture wasconcentrated in vacuo and crude A-1-ii suspended in 200 mL methanol andreacted with N-[(1,3-dimethyl-2,4,6(1H,3H,5H)-trioxopyrimidin-5-ylidene) methyl]-N′,N″-dimethylamine (23.6mmol) at 50° C. (pH 9.0) until completion. After evaporation and drying,crude A-1-iii was reacted with 150 mL acetylation mixture(pyridine/Ac₂O, 2/1, v/v) until completion, concentrated in vacuo,coevaporated with toluene and dried. The residue was suspended in ethylacetate and extracted with water, 10% aqueous HCl, saturated, aqueousNaHCO₃ solution and H₂O, dried over Na₂SO₄ and concentrated. The cruderesidue was dissolved in dry methanol and reacted with a catalyticamount of NaOMe. After completion, the reaction was neutralized withAmberlite IR 120 and filtered. The organic layer was evaporated anddried to furnish the title compound A-1-iii in 70% yield (over 4 steps).

Preparation of A-1-iv-a:

Methyl-2-deoxy-2-N-[1-(1,3-dimethyl-2,4,6(1H,3H,5H)-trioxopyrimidin-5-ylidene)methyl]-α-D-glucopyranoside A-1-iii (16.0 g, 44.5 mmol) in acetonitrile(200 mL) was reacted with benzaldehyde dimethyl acetal (14.0 mL, 92.3mmol) and a catalytic amount of p-toluenesulphonic acid monohydrate.After 2 hours at 55° C., the mixture was neutralized and evaporated. Theremaining residue was extracted, washed and evaporated.

Yield: 18.3 g (92%), R_(f)=0.20 (1,2-dichloroethane/ethylacetate=7/3).

Preparation of A-1-v-a:

Methyl-4,6-O-benzylidene-2-deoxy-2-N-[1-(1,3-dimethyl-2,4,6(1H, 3H,5H)-trioxopyrimidin-5-ylidene) methyl]-α-D-glucopyranoside A-1-iv-a(18.30 g, 40.90 mmol) in DMF (50 mL) was reacted with ethylenediamine(20 mL) at room temperature. After stirring for 35 minutes, the mixturewas concentrated. Yield: 10.90 g (94.7%), R_(f)=0.18(chloroform/methanol=9/1).

Preparation of A-1-vi-a:

To a solution ofmethyl-2-amino-4,6-O-benzylidene-2-deoxy-α-D-glucopyranoside (7.5 g,26.7 mmol) and 4-N,N′-(dimethylamino)pyridine (14.5 g) in acetonitrile(100 mL) was added TfN₃-solution (85 mL) at room temperature. Thereaction mixture was concentrated and the residue was purified byfiltration through a short silica gel pad.

Yield: 7.00 g (85.3%), R_(f)=0.18 (chloroform/methanol=9/1).

Preparation of A-1-vii-a:

Methyl 2-azido-2-deoxy-4,6-benzylidene-α-D-glucopyranoside A-1-vii-a(10.87 g, 35.40 mmol) in N,N′-dimethylformamide (50 mL) was reacted withNaH (95%, 0.92 g, 36.4 mmol) and benzyl bromide (5.47 mL, 45.9 mmol).After completion, the excess of NaH was quenched, followed byconcentration. The residue was extracted, washed and concentrated.

Yield: 12.93 g (92.0%), R_(f)=0.37 (petroleum spirit/ethyl acetate=3/1).

Preparation of A-1:

Methyl-2-azido-3-O-benzyl-2-deoxy-α-D-glucopyranoside (9.87 g, 31.9mmol) in dichloromethane (50 mL) and pyridine (10 mL) was treated withbenzoyl chloride (3.72 mL, 32.04 mmol) at −45° C. for 2 hours. Thereaction was concentrated and the residue extracted, washed andevaporated.

Yield: 10.78 g (81.7%), R_(f)=0.31 (petroleum spirit/ethylacetate=1/1).

Compound A-1:

¹H-NMR (400 MHz, CDCl₃): δ=8.03 (d, 2H, Aryl), 7.57 (m, 1H, Aryl),7.45-7.29 (m, 7H, Aryl), 4.93 (d, 1H, J_(gem)=10.8 Hz, OCH₂), 4.82 (d,1H, J_(gem)=10.8 Hz, OCH₂), 4.81 (d, 1H, J_(1,2)=3.6 Hz, H-1α), 4.73(dd, 1H, J_(5,6a)=4.4 Hz, J_(gem)=12.0 Hz, H-6a), 4.47 (dd, 1H,J_(5,6b)=2.0 Hz, H-6b), 3.85 (dd, 1H, J_(3,4)=8.8 Hz, H-3), 3.57 (ddd,1H, J_(4,5)=10.0 Hz, H-4), 3.45 (s, 3H, Ome), 3.37 (dd, 1H, J_(2,3)=10.0Hz, H-2), 2.80 (bs, 1H, 4-OH).

Example 2 Synthesis of Building Blocks A-3 and A-4

Example 2: Synthesis of building block A-3 and A-4, conditions: a) SOP7, (72% for R═H); b) SOP 4, (82%); c) SOP 17, (84%); d) SOP 5.

Compound A-3:

¹H-NMR (400 MHz, CDCl₃): δ=10.16 (dd, 1H, J_(NH,2)=9.4 Hz,J_(NH,═C—H)=14.0 Hz, NH), 8.11 (d, 1H, ═C—H), 7.68-7.22 (3m, 8H, Aryl),4.84 (d, 1H, J_(1,2)=3.5 Hz, H-1α), 4.83 (dd, 1H, J_(6a,6b)=12.3 Hz,J_(5,6a)=3.5 Hz, H-6a), 4.73 (d, 1H, J_(gem)=11.7 Hz, OCH₂), 4.46 (dd,1H, J_(5,6b)=2.1 Hz, H-6b), 3.91 (m, 1H, H-5), 3.72 (dd, 1H,J_(3,4)≈J_(2,3)=8.8 Hz, H-3), 3.57 (ddd, 1H, J_(4,5)=9.5 Hz, H-4), 3.48(s, 3H, Ome), 3.38 (ddd, 1H, J_(2,3)=10.5 Hz, H-2), 3.32 (s, 3H, Nme),3.31 (s, 3H, Nme), 3.05 (bs, 1H, 4-OH).

Example 3 Synthesis of L-ido Configured Cilycosyl Donor B-1

Example 3: Synthesis of Building Block B-1, conditions: a) SOP 7, (95%);b) 60% aqueous Acetic acid, 60° C. (90%); c) Methanesulfonyl chloride,Pyridine, 0° C.-RT (87%); d) Cesium Acetate, Ac₂O, 120° C. (95%); e) SOP22, (92%); f) 1.90% TFA, 0° C.; 2. Ac₂O, Pyridine; 3. SOP 31, (73%, 3steps); g) SOP 22, (98%); h) SOP 3, (92%); l) SOP 18, (98%); j) 80%acetic acid, 100° C. (98%); k) SOP 26, (89%); I) SOP 23, (98%).

Preparation of B-1-iii:

B-1-ii (15.60 mmol) was dissolved in 60% aqueous acetic acid (50 mL) andstirred at 60° C. until completion. After neutralization with solidNaHCO₃, the mixture was evaporated and co evaporated with toluene. CrudeB-1-iii was dissolved in CHCl₃/H₂O, the organic layer separated, driedover Na₂SO₄ and evaporated. The remaining residue was purified by ashort silica gel chromatography to yield B-1-iii in 90% (4.36 g).

Preparation of B-1-iv:

17.72 mmol of B-1-iii was dissolved in 25 mL dry pyridine, to whichmesyl chloride (methylsulfonyl chloride, 42.5 mmol) was added dropwiseat 0° C. The mixture was stirred at 4° C. until completion and wassubsequently poured into warm water (50° C., 90 mL), cooled and theprecipitate isolated by filtration. B-1-iv was obtained after drying in87% yield (7.19 g).

Preparation of B-1-v:

B-1-iv (6.43 mmol) and cesium acetate (64.3 mmol) were suspended in 25mL acetic anhydride and refluxed at 125° C. until completion. Thereaction mixture was concentrated in vacuo, co evaporated with tolueneand the residue extracted from ethyl acetate/H₂O (1/1). The organiclayer was collected and washed with saturated aqueous NaHCO₃ solutionand saturated brine solution, dried over Na₂SO₄ and evaporated.Purification was achieved by silica gel chromatography. Yield: 2.68 g(95%).

Preparation of B-1-vii:

B-1-vi (5.61 mmol) was dissolved in aqueous TFA (90%, 15 mL) and furtherstirred at 0° C. until completion. The reaction mixture was neutralizedwith aqueous NaOH solution at 0° C., concentrated in vacuo and dried.The residue was suspended in 90 mL acetylation mixture (pyridine/aceticanhydride=2/1) and 50 mL dichloromethane at 0° C. and further stirreduntil completion. After concentration in vacuo and co evaporation withtoluene, the residue was dissolved in ethyl acetate/H₂O (1/1), theorganic layer collected and washed with 10% aqueous citric acidsolution, saturated aqueous NaHCO₃ solution and brine solution, driedover Na₂SO₄ and evaporated. The crude residue and p-thiocresol (6.0mmol) were dissolved in 40 mL anhydrous dichloromethane and cooled to 0°C., reacted with BF₃×OEt₂ (8.41 mmol) and further stirred at r.t. untilcompletion. The reaction was stopped with saturated NaHCO₃ solution andthe organic layer was washed with water, dried over Na₂SO₄ andevaporated. Final purification was achieved by silica gel chromatographyto yield B-1-vii in 73% over 3 steps.

Preparation of B-1-xi:

B-1-x (8.0 mmol) was dissolved in 80% aqueous AcOH and heated at 100° C.until completion. The mixture was cooled to r.t., neutralized with solidNaHCO₃ and dissolved in ethyl acetate/water (1/1). After removal of theaqueous layer, the organic layer was dried over MgSO₄ and evaporated todryness furnishing B-1-xi in 98% yield.

Compound B-1:

¹H-NMR (400 MHz, CDCl₃): δ=8.07 (d, 2H, Aryl), 7.57-7.30 (m, 10H, Aryl),7.10 (d, 2H, Aryl), 6.88-6.81 (m, 4H, Mp), 5.55 (d, 1H, J_(1,2)<1.5 Hz,H-1β), 5.45 (m, 1H, H-2), 5.26 (ddd, 1H, H-5), 5.13 (m, 1H, H-4), 4.91(d, 1H, J_(gem)=12.1 Hz, OCH₂), 4.78 (d, 1H, J_(gem)=12.1 Hz, OCH₂),4.16 (dd, 1H, J_(gem)=9.6 Hz, J_(5,6a)=7.6 Hz, H-6a), 4.08 (dd, 1H,J_(5,6b)=5.2 Hz, H-6b), 3.93 (m, 1H, H-3), 3.77 (s, 3H, OCH₃), 2.58-2.36(m, 4H, (CH₂)₂ Lev), 2.32 (s, 3H, SCH₃), 2.05 (s, 3H, CH₃C═O).

Example 4 Synthesis of L-ido Configured Gilycosyl Donor B-2

Example 4: Synthesis of L-ido Configured Glycosyl Donor B-2; a) SOP 2;b) SOP 18; c) SOP 5; d) SOP 23.

Example 5 Synthesis of Building Block C-1, C-1a and C-1b

Example 5: Synthesis of Building Blocks C-1, C-1a and C-1b, conditions:a) SOP 19; b) SOP 13, (78%, 2 steps); c) SOP 8, (91%); d) SOP 22; e) SOP2, (85%, 2 steps for C-1-vi); f) SOP 18; g) SOP 5, (75%, 2 steps forC-1).

Preparation of C-1-iia:

To methyl 2-azido-2-deoxy-1-thio-β-D-glucopyranoside. (10 g, 42.50 mmol)in pyridine (50 mL) at 0° C. was added acetic anhydride (20 g) and thereaction stirred for 1 hour. The reaction mixture was evaporated todryness and the residue extracted to give the title triacetate (15.23 g,quantitative,), R_(f)=0.7 (CHCl₃/Petroleum ethers, 1:1).

Preparation of C-1-iii:

To a solution of methyl3,4,6-tri-O-acetyl-2-azido-2-deoxy-1-thio-β-D-glucopyranoside (14.1 g,39 mmol) in wet acetone (200 mL) was added NBS (3 equiv.). The resultingmixture was allowed to stir for 2 h. The mixture was then quenched,concentrated and the residue purified by silica gel chromatography togive the title hemiacetal as an oil (10.1 g, 78%), R_(f)=0.5(EtOAc/Petroleum ether, 1:1).

Preparation of C-1-vi:

A mixture of 2-azido-2-deoxy-β-D-glucopyranosyl tert-butyldiphenylsilane(5.5 g, 12.42 mmol), 4-methoxybenzaldehyde dimethylacetal (4.4 g, 24mmol), and 4-toluenesulphonic acid (100 mg) in acetonitrile/DMF (200 mL,5:3) were heated at 60° C. for 1 hour. The reaction mixture was thenneutralized and evaporated to give the crude compound as an oil. Theresidue was purified by silica chromatography to give the product (6.7g, 96%, 85% from C-1-iv); R_(f)=0.8 (dichloromethane/Petroleum ethers;10:2).

Preparation of C-1-vii:

A mixture of DMAP (1.63 g, 13.2 mmol) and benzoyl chloride (1.7 g, 12.1mmol) and2-azido-2-deoxy-4,6-O-(4-methoxybenzylidene)-β-D-glucopyranosyltert-butyldiphenylsilane (6.7 g, 11.9 mmol) in 1,2-dichloroethane (100mL) was stirred at 60° C. for 1 h. The reaction mixture was quenched,extracted, washed and concentrated to give a crude residue. The residuewas passed through a plug of silica to give the product (5.5 g, 69%);R_(f)=0.7 (dichloromethane/Petroleum ethers; 4:1).

Preparation of C-1:

To a mixture of2-azido-2-deoxy-3-O-benzoyl-4,6-O-(4-methoxybenzylidene)-β-D-glucopyranosyltert-butyldiphenylsilane (10 g, 15 mmol), sodiumcyanoborohydride (5 g,75.6 mmol) and molecular sieves in DMF (200 mL) at 0° C. was addedtrifluoroacetic acid (28 g, 247 mmol) at 0° C. and then left to runovernight at r.t. The reaction mixture was quenched, filtered andconcentrated and the residue purified by column chromatography to givethe title compound (7.0 g, 70%), R_(f)=0.4 (ethylacetate/petroleumethers, 3:7).

Compound C-1:

¹H-NMR (400 MHz, CDCl₃): δ=8.08 (d, 2H, Aryl), 7.72 (m, 4H, Aryl), 7.59(m, 1H, Aryl), 7.47 (m, 3H, Aryl), 7.42 (m, 2H, Aryl), 7.34 (m, 3H,Aryl), 7.13 (d, 2H, Mpm) 6.83 (d, 2H, Mpm), 4.96 (dd, 1H,J_(2,3)≈J_(3,4)=9.7 Hz, H-3), 4.53 (d, 1H, J_(1,2)=7.6 Hz, H-1β), 4.37(2d, 2H, OCH₂), 3.83 (ddd, 1H, H-4), 3.79 (s, 3H, OCH₃), 3.65 (dd, 1H,H-2), 3.53 (dd, 1H, J_(gem)=10.8 Hz, J_(5,6a)=4.1 Hz, H-6a), 3.46 (dd,1H, J_(5,6b)=4.1 Hz, H-6b), 3.12 (m, 1H, H-5), 3.02 (d, 1H, J_(4,OH)=3.5Hz, 4-OH), 1.12 (s, 9H, C(CH₃)₃).

Example 6 Synthesis of Building Block C-2

Example 6: Synthesis of Building Block C-2, conditions: a) SOP 1, (90%for R=SMe); b) SOP 18, (87% for R=SMe); c) SOP 4, p-TosOH, MeOH, CH₃CN(86% for R=SMe); d) SOP 17, (92% for R=SMe); e) SOP 13, (94%); f) SOP 8,(82%).

Compound C-2:

¹H-NMR (400 MHz, CDCl₃): δ=8.09 (d, 2H, Aryl), 7.97 (d, 2H, Aryl), 7.72(m, 4H, Aryl), 7.60 (m, 1H, Aryl), 7.50-7.27 (m, 11H, Aryl), 4.98 (dd,1H, J_(2,3)≈J_(3,4)=9.7 Hz, H-3), 4.58 (d, 1H, J_(1,2)=7.8 Hz, H-1β),4.51 (dd, 1H, J_(gem)=11.3 Hz, J_(5,6a)=4.7 Hz, H-6a), 4.36 (dd, 1H,J_(5,6b)=2.2 Hz, H-6b), 3.72-3.68 (m, 2H, H-2, H-4), 3.31 (m, 1H, H-5),3.23 (d, 1H, J_(4,OH)=4.5 Hz, 4-OH), 1.13 (s, 9H, C(CH₃)₃).

Example 7 Synthesis of Several Carbamoylated Building Blocks C-3a toC-3d and C-4a to C-4-d, Containing a 6-0 benzoyl or 6-O-p-methoxybenzylProtection

Example 7: Synthesis of several carbamoylated building blocks C-3a toC-3d and C-4a to C-4-d, containing a 6-O-benzoyl or 6-O-p-methoxybenzylprotection, conditions: a) R=MeO: SOP 2; R═H: SOP 1, (82%, R¹=SCres,R═H); b) SOP 30, (87%, R¹=SCres, R═H); c) SOP 29, (95%, R¹=SCres, R═H);d) SOP 4, (72%, R¹=SCres); e) SOP 17, (85%); f) SOP 5.

Compound C-3a:

¹H-NMR (400 MHz, CDCl₃): δ=8.06 (d, 2H, Aryl), 7.62 (m, 1H, Aryl), 7.48(t, 2H, Aryl), 7.38 (d, 2H, Aryl), 6.97 (d, 2H, Aryl), 5.06 (bs, 1H,NH), 4.79 (dd, 1H, J_(gem)=12.0 Hz, J_(5,6a)=3.6 Hz, H-6a), 4.70 (d, 1H,J_(1,2)=9.2 Hz, H-1β), 4.63 (dd, 1H, J_(5,6b)=2.0 Hz, H-6b), 4.18 (dd,1H, J_(2,3) J_(3,4)=10.4 Hz, H-3), 3.89 (dd, 1H, J_(4,5)=9.2 Hz, H-4),3.72 (m, 1H, H-5), 3.23 (ddd, 1H, H-2), 3.12 (bs, 1H, 4-OH), 2.29 (s,3H, SCH₃).

Example 8 Synthesis of Several 6-Omp and Cyclic 2,3-carbamoyl ProtectedBuilding Blocks C-5a to C-5c

Example 8: Synthesis of several 6-OMp and cyclic 2,3-carbamoyl protectedbuilding blocks C-5a to C-5c, conditions: a) SOP 18, (92% forR¹=OTBDPS); b) SOP 4, (82%); c) SOP 26, (75% for R¹=OTBDPS); d) SOP 30,(87%); e) SOP 29, (95%).

Compound C-5c:

¹H-NMR (400 MHz, CDCl₃): δ=7.69 (m, 2H, Aryl), 7.63 (m, 2H, Aryl),7.46-7.31 (m, 6H, Aryl), 6.82 (bs, 4H, Mp), 5.04 (bs, 1H, NH), 4.78 (d,1H, J_(1,2)=7.6 Hz, H-1β), 4.15-4.10 (m, 3H, H's not assigned), 3.97(dd, 1H, J=11.6 Hz, J=9.6 Hz, H not assigned), 3.78 (s, 3H, OMe), 3.56(m, 1H, H not assigned), 3.48 (m, 1H, H not assigned), 2.80 (bs, 1H,4-OH), 1.08 (s, 9H, C—(CH₃)₃).

Example 9 Synthesis of Building Blocks C-6-a and C-6-b and C-7

Example 9: Synthesis of building blocks C-6-a, C-6-b and C-7,conditions; a) SOP 12, (83%); b) SOP 7; c) SOP 5, (75%, 2 steps); d) SOP14 (82%); e) SOP 8 (91%).

Compound C-6-a:

¹H-NMR (400 MHz, CDCl₃): δ=7.43 (d, 2H, Aryl), 7.25 (m, 4H, Aryl), 7.08(d, 2H, Aryl), 6.88 (m, 4H, Aryl), 4.81 (d, 1H, J_(gem)=10.8 Hz, OCH₂),4.74 (d, 1H, J_(gem)=10.8 Hz, OCH₂), 4.53 (d, 1H, J_(gem)=11.1 Hz,OCH₂), 4.48 (d, 1H, J_(gem)=10.8 Hz, OCH₂), 4.35 (d, 1H, J_(1,2)=10.0Hz, H-1β), 3.82 (s, 3H, OCH₃), 3.79 (s, 3H, OCH₃), 3.76 (dd, 1H,J_(gem)=10.5 Hz, J_(5,6a)=5.4 Hz, H-6a), 3.70 (dd, 1H, J_(5,6b)=5.4 Hz,H-6b), 3.56 (ddd, 1H, H-4), 3.42 (m, 1H, H-5), 3.34 (dd, 1H, J_(3,4)=8.8Hz, H-3), 3.24 (dd, 1H, J_(2,3)=9.4 Hz, H-2), 2.72 (d, 1H, J_(4,OH)=3.5Hz, 4-OH), 2.38 (s, 3H, SCH₃).

Compound C-7:

¹H-NMR (400 MHz, CDCl₃): 7.63 (d, 4H, Aryl), 7.35-7.21 (m, 8H, Aryl),7.08 (m, 2H, Aryl), 6.83-6.78 (m, 4H, Aryl), 4.72 (d, 1H, J_(gem)=11.0Hz, OCH₂), 4.59 (d, 1H, J_(gem)=11.0 Hz, OCH₂), 4.29 (d, 1H, J_(1,2)=7.8Hz, H-1β), 4.27 (d, 1H, J_(gem)=11.7 Hz, OCH₂), 4.21 (d, 1H,J_(gem)=11.7 Hz, OCH₂), 3.72 (s, 3H, OCH₃), 3.71 (s, 3H, OCH₃), 3.51(ddd, 1H, J_(3,4)≈J_(4,5)=8.6 Hz, H-4), 3.40-3.32 (m, 3H, H-6a, H-6b,H-2), 3.05 (dd, 1H, J_(2,3)=9.8 Hz, H-3), 2.90 (m, 1H, H-5), 2.51 (d,1H, J_(4,OH)=2.2 Hz, 4-OH), 1.12 (s, 9H, C(CH₃)₃).

Example 10 Synthesis of Building Block C-8a to C-8c

Example 10: Synthesis of building blocks C-8a to C-8c, conditions: a)SOP 7, AllBr, DMF (65%, R=OTBDPS); b) SOP 4, (86%, R=OTBDPS); c) SOP 26,(70%, R=OTBDPS); d) SOP-30; e) SOP 12, (70%, 2 steps for R=OTBDPS).

Compound C-8c:

¹H-NMR (400 MHz, CDCl₃): δ=7.72 (m, 4H, Aryl), 7.43-7.16 (m, 6H, Aryl),6.76 (m, 4H, Mp), 5.96 (m, 1H, ═CH Allyl), 5.31 (m, 1H, ═CH Allyl), 5.22(m, 1H, ═CH Allyl), 4.42 (d, 1H, J_(1,2)=7.6 Hz, H-1β), 4.39 (m, 1H,OCH₂ Allyl), 4.23 (m, 1H, OCH₂ Allyl), 3.97 (dd, 1H, J_(gem)=10.0 Hz,J_(5,6a)=3.6 Hz, H-6a), 3.92 (dd, 1H, J_(5,6b)=5.2 Hz, H-6b), 3.77 (s,3H, OCH₃), 3.66 (ddd, 1H, J_(4,5)≈J_(3,4)=9.4 Hz, H-4), 3.42 (dd, 1H,J=9.8 Hz and J=7.8 Hz, H not assigned), 3.22 (m, 1H, H-5), 3.09 (dd, 1H,J=8.4 Hz and J=9.6 Hz, H not assigned), 2.48 (d, 1H, J_(4,OH)=2.8 Hz,4-OH), 1.12 (s, 9H, C(CH₃)₃).

Example 11 Synthesis of Building Block D-1

Example 11: Synthesis of building block D-1; a) SOP 1, (95%); b) SOP 7,(85%); c) SOP 13, (92%); d) SOP 8; e) SOP 4, (70%, 2 steps); f) 1. SOP15; 2. SOP 16, (75%, 2 steps).

Compound D-1:

¹H-NMR (400 MHz, CDCl₃): δ=7.72 (m, 4H, Aryl), 7.41 (m, 2H, Aryl),7.32-7.25 (m, 14H, Aryl), 5.04 (d, 1H, J_(gem)=11.0 Hz, OCH₂), 4.81 (m,3H, OCH₂), 4.63 (d, 1H, J_(1,2)=7.4 Hz, H-1β), 3.88 (ddd, 1H,J_(3,4)≈J_(4,5)=9.2 Hz, H-4), 3.70 (s, 3H, OCH₃), 3.53 (dd, 1H, J=7.5Hz, J=9.0 Hz, H not assigned), 3.47 (d, 1H, J_(4,5)=9.8 Hz, H-5), 3.42(dd, 1H, J=8.9 Hz and J=8.9 Hz, H not assigned), 2.87 (d, 1H,J_(4,OH)=2.4 Hz, 4-OH), 1.11 (s, 9H, C(CH₃)₃).

Example 12 Synthesis of Building Block D-2a 2-O-AllyloxycarbonylProtected Thioethyl Glycoside

Example 12: Synthesis of Building Block D-2, conditions: a) 1. SOP 22;2. SOP 1; b) SOP 7; c) 1. SOP 4; 2. TritCl, Pyridine, (ClCH₂)₂; 3. SOP23; d) 1. CrO₃, H₂SO₄, Acetone, 0° C., 2. SOP 16; e) 1. Dimethyldioxirane, Acetone; 2. EtSH, TFAA, CH₂Cl₂, 3. SOP 35.

Example 13 Synthesis of Building Block D-3

Example 13: Synthesis of Building Block D-3, conditions: a) 1. SOP 4,Amberlite IR 120, H₂O, 80° C.; 2. SOP 18, (85%, 2 steps) b) 1. SOP 21;2. SOP 8, (70%, 2 steps); c) SOP 22, (96%); d) 1. SOP 15; 2. SOP 16,(80%, 2 steps); e) SOP 23, (92%); f) SOP 9, (95%); g) SOP 25a, (91%).

Preparation of D-3-I, Step 1:

The starting material (57 mmol) and Amberlite IR 120 iron exchange resin(H⁺-form, 20 g) were suspended in water (180 mL) and stirred at 80° C.until completion. The iron exchange resin was removed by filtration andextracted with water. The combined aqueous layers were neutralized withtriethyl amine and freeze dried.

Compound D-3-v:

¹H-NMR (400 MHz, CDCl₃): δ=7.95 (m, 2H, Aryl), 7.68 (m, 2H, Aryl),7.58-7.12 (m, 16H, Aryl), 5.47 (dd, J_(1,2)=7.6 Hz, J_(2,3)=9.6 Hz,H-2), 5.31 (dd, J_(3,4)=9.6 Hz, H-4), 4.64 (d, 1H, 7.6 Hz, H-1β), 4.60(d, 1H, J_(gem)=12.0 Hz, OCH₂), 4.55 (d, 1H, J_(gem)=12.0 Hz, OCH₂),3.74 (dd, 1H, H-3), 3.70 (s, 3H, OCH₃), 3.63 (d, 1H, J_(4,5)=9.6 Hz,H-5), 2.68-2.16 (m, 4H, (CH₂)-Lev), 2.15 (s, 3H, CH₃), 0.96 (s, 9H,C(CH₃)₃).

Example 14 Syntheses of a Range of Block D Donor Sugars D-4 to D-7 froma Common Intermediate, a 4-O-levulinoyl Glucal

Example 14: Syntheses of D-4 to D-7 as donor sugars, conditions: a) 1.Dimethyl dioxirane, Acetone; 2. TBAF, THF; 3. SOP 35; b) 1. Dimethyldioxirane, Acetone; 2. 4-penten-1-ol, ZnCl₂, CH₂Cl₂; 3. SOP 35; c) 1.Dimethyl dioxirane, Acetone; 2. ArSH, TFAA, CH₂Cl₂, (Ar=Ph, p-Tol); 3.SOP 35 or (ClAc)₂O, Pyridine, CH₂Cl₂ (for D-6b); d) MCPBA, CH₂Cl₂ (forD-6b as substrate).

Example 15 Synthesis of Building Block E-1 to E-4

Example 15: Synthesis of Building Block E-1 to E-4, conditions: a) SOP8; b) SOP 7; c) SOP 9, (84% over 3 steps, R=SMe); d) SOP 18, (82%,R=SMe); e) 1. SOP 13, (75%, for E-1-iv-a as starting material); 2. SOP25b, (88%); f) 1. TosCl, Pyridine; 2. p-MeO—C₆H₄—O Na, NMP, 60° C.; g)SOP 7, (78%, R=SMe); h) 1. SOP 14; 2. SOP 25b, (79%, 2 steps, R=SMe).

Preparation of E-1-1-a:

A mixture of methyl 2-azido-2-deoxy-thio-β-D-glucopyranoside (10 g, 42.5mmol) and imidazole (4.9 g, 71.25 mmol) in 20 mL DMF was treated withtert-butyldiphenylchlorosilane (11.6 mL, 44.63 mmol) for 2 h. Thereaction mixture was concentrated, extracted, washed and dried. Yield:23 g (crude light yellow syrup), R_(f)=0.74 (CHCl₃/methanol=9/1).

Preparation of E-1-ii-a:

The silyl ether from the previous step in 50 mL DMF, was treated with2.68 g of 95% NaH (106.25 mmol) and 12.64 mL (106.25 mmol) of benzylbromide at 0° C. After 1 h the excess NaH was quenched and the reactionconcentrated, extracted, washed and concentrated to afford a yellowsyrup yield: 28.5 g (crude yellow syrup), R_(f)=0.80 (hexane/ethylacetate=7/3).

Preparation of E-1-iii-a:

The crude yellow syrup from the above reaction was treated with 36.5 mLAcOH and 106.3 mL (106.25 mmol) of 1 M solution of TBAF in THFovernight. The reaction was concentrated and purified by chromatographyto afford the title compound. 14.9 g (84%, 3 steps) R_(f)=0.36(petroleum spirit/ethyl acetate=7/3)

Preparation of E-1-iv-a:

Methyl 2-azido-2,3 di-O-benzyl-2-deoxy-thio-β-D-glucopyranoside (14.5 g,34.9 mmol) in dichloromethane (200 mL) and anhydrous pyridine (8.6 mL,106.2 mmol) was treated with benzoylchloride (4.93 mL, 42.5 mmol) at 0°C. for 1 hour. The reaction mixture was quenched, extracted, washed andevaporated. The residue was purified by silica gel column chromatographyto afford the title compound as a white solid.

Yield: 14.9 g (82%), R_(f)=0.82 (Petroleum spirit/Ethyl acetate=7/3).

Preparation of E-1:

Methyl2-azido-6-O-benzoyl-2,3-di-O-benzyl-2-deoxy-thio-β-D-glucopyranoside(8.68 g, 16.7 mmol) in acetone (50 mL) was treated withN-bromosuccinimide (8.92 g, 50.12 mmol) at 0° C. for 1 hour. Thereaction mixture was then quenched, extracted, washed and evaporated,furnishing a yellow syrup which was purified by chromatography. Yield:6.13 g (75%), R_(f)=0.57 (Petroleum spirit/Ethyl acetate=7/3). A cooledmixture of 2-azido-6-O-benzoyl-2,3di-O-benzyl-2-deoxy-α/β-D-glucopyranose (5 g, 10.2 mmol), K₂CO₃ (7.0 g,51 mmol) and trichloroacetonitrile (5.1 mL, 51 mmol) in 30 mL ofdichloromethane was stirred for 2 h. The mixture was then filteredthrough celite and the filtrate was concentrated and purified on a shortcolumn of silica gel to obtain the title compound as an amorphous whitesolid.

Yield 5.69 g (88%), R_(f)=0.85 (Petroleum spirit/Ethyl acetate=7/3).

Compound E-1:

¹H-NMR (400 MHz, CDCl₃): δ=8.73 (s, 1H, C═NH), 8.00 (m, 2H, Aryl), 7.56(m, 1H, Aryl), 7.43-7.25 (m, 12H, Aryl), 5.66 (d, 1H, J=8.4 Hz, H-1β),4.95 (d, 1H, J_(gem)=10.8 Hz, OCH₂), 4.87 (d, 2H, J=10.8 Hz, OCH₂), 4.62(d, 2H, J_(gem)=10.8 Hz, OCH₂), 4.58 (dd, 1H, J_(gem)=12.4 Hz,J_(5,6a)=2.0 Hz, H-6a), 4.46 (dd, 1H, J_(5,6b)=3.6 Hz, H-6b), 3.77-3.72(m, 3H, H-5, 2H not assigned), 3.62 (dd, 1H, J=8.3 Hz, J=9.7 Hz, H notassigned).

Compound E-2:

¹H-NMR (400 MHz, CDCl₃): δ=8.70 (s, 1H, C═NH), 7.38-7.22 (m, 10H, Aryl),7.13 (m, 2H, Aryl), 6.83 (d, 2H, Mpm), 6.44 (d, 1H, J_(1,2)=3.5 Hz,H-1α), 4.93 (d, 1H, J_(gem)=10.5 Hz, OCH₂), 4.89 (d, 1H, J_(gem)=10.5Hz, OCH₂), 4.78 (d, 1H, J_(gem)=10.5 Hz, OCH₂), 4.57 (d, 1H,J_(gem)=11.7 Hz, OCH₂), 4.51 (d, 1H, J_(gem)=11.7 Hz, OCH₂), 4.39 (d,1H, J_(gem)=11.7 Hz, OCH₂), 4.02 (dd, 1H, J_(3,4)≈J_(2,3)=9.5 Hz, H-3),3.98 (m, 1H, H-5), 3.86 (dd, 1H, J_(4,5)=9.6 Hz, H-4), 3.76 (dd, 1H,H-2), 3.75 (s, 3H, OCH₃), 3.69 (dd, 1H, J_(5,6a)=3.5 Hz, J_(gem)=10.5Hz, H-6a), 3.63 (dd, 1H, J_(5,6b)=1.8 Hz, H-6b).

Example 16 Synthesis of Building Blocks E-5 to E-8

Example 16: Syntheses of Building Blocks E-5 to E-8, conditions: a) SOP6, (85%, R=SMe); b) SOP 30, (86%, R=SMe); c) SOP 10, (88%, R=SMe); d)SOP 18, (92%, R=SMe); e) 1. SOP 13; 2. SOP 25b, (85%, 2 steps, R=SMe);f) SOP 7; g) 1. SOP 14; 2. SOP 25b; h) 1. TsCl, DMF; 2. p-MeO—C₆H₄—O Na,NMP, 60° C.; i) SOP 8.

Compound E-5:

¹H-NMR (400 MHz, CDCl₃): δ=10.20 (dd, 1H, J_(NH,═C—H)=14.0 Hz,J_(NH,H-)2=9.9 Hz, NH), 8.80 (s, 1H, C═NH), 8.16 (d, 1H, ═C—H), 7.99 (m,2H, Aryl) 7.58 (m, 1H, Aryl), 7.45 (m, 2H, Aryl), 7.30-7.17 (m, 10H,Aryl), 6.42 (d, 1H, J_(1,2)=3.6 Hz, H-1α), 4.89 (d, 1H, J_(gem)=8.4 Hz,OCH₂), 4.68-4.60 (m, 3H, OCH₂), 4.58 (dd, 1H, J_(5,6a)=2.0 Hz,J_(gem)=12.4 Hz, H-6a), 4.51 (dd, 1H, J_(5,6b)=4.0 Hz, H-6b), 4.22 (m,1H, H-5), 4.03 (dd, 1H, J_(3,4)≈J_(2,3)=9.6 Hz, H-3), 3.80 (dd, 1H,J_(4,5)=9.4 Hz, H-4), 3.70 (ddd, 1H, H-2), 3.32 (s, 3H, NCH₃), 3.25 (s,3H, NCH₃).

Example 17 Preparation of L-Iduronic Acid Containing Disaccharides B-A-1to B-A-10

Example 17: Preparation L-iduronic acid containing disaccharides B-A-1to B-A-10; a) SOP 32a, (76%, for B-A-1); b) SOP 27, (88%, for B-A-5); c)1.50P 20; 2. SOP 16, (84% for B-A-7, 2 steps); d) SOP 24, (94%, forB-A-9).

Formation of Disaccharide B-A-1 (Step a)

A suspension of A-1 (410 mg, 992 μmol), B-1 (680 mg, 992 μmol) andfreshly activated molecular sieves 4 Å (1.0 g) in dry CH₂Cl₂ (20 mL) wasstirred for 90 min at 0° C. N-Iodosuccinimide (405 mg, 1.8 mmol) wasadded and stirring continued for 20 min. After addition oftrifluoromethanesulfonic acid (10.6 μl, 119.7 μmol), the reactionmixture was further stirred until completion (from 0° C. to 25° C.) andquenched with aqueous NaHCO₃-solution (10%). The mixture was dilutedwith CH₂Cl₂ and filtered through a celite pad. The filtrate was washedwith a 10% KHCO₃/Na₂S₂O₃ solution, water and saturated brine solution,dried over MgSO₄ and evaporated. Final purification was achieved bysilica gel column chromatography. Yield: 730 mg (76%).

Formation of Disaccharide B-A-7(Step c)

Disaccharide B-A-5 (1.00 g, 1.15 mol) was dissolved in anhydrous DMF(7.0 mL) and reacted with pyridinium dichromate (4.33 g, 11.5 mmol)under stirring at room temperature until complete conversion into theuronic acid. The reaction mixture was subsequently poured into 50 mLwater and the whole extracted with diethyl ether. The combined etherlayers were washed with 10% aqueous citric acid solution, filteredthrough a short silica gel pad, dried over MgSO₄, evaporated and driedunder high vacuum. The crude residue was dissolved in Toluene (3 mL) andmethanol (3 mL) and titurated with TMSCHN₂ solution (2M in hexane) untilcompletion. The excess of TMSCHN₂ was destroyed by addition of aceticacid and the mixture evaporated. Final purification was achieved viasilica gel chromatography.

Yield: 871 mg (84%).

Compound B-A-9:

¹H-NMR (400 MHz, CDCl₃): δ=8.03 (m, 2H, Aryl), 7.91 (m, 2H, Aryl), 7.53(m, 2H, Aryl), 7.42-7.23 (m, 14H, Aryl), 5.37 (d, 1H, J_(1,2)<1.5 Hz,H-1′α), 5.21 (m, 1H, H-2′), 4.97 (d, 1H, J_(4,5)=2.3 Hz, H-5′), 4.84 (d,2H, J_(gem)=10.8 Hz, OCH₂), 4.81 (d, 1H, J_(gem)=10.8 Hz, OCH₂), 4.80(d, 1H, J_(1,2)=3.6 Hz, H-1′α), 4.77 (1H, J_(5,6a)=1.8 Hz, H-6a), 4.70(m, 2H, OCH₂), 4.47 (dd, 1H, J_(5,6b)=4.2 Hz, J_(gem)=12.3 Hz, H-6b),4.05-3.97 (m, 3H, H-4′, H-4, H-5), 3.91-3.87 (m, 2H, H-3′, H-3), 3.49(s, 3H, OCH₃), 3.44 (m, 1H, H-2), 3.43 (s, 3H, OCH₃).

Selected ¹³C-NMR (100 MHz, CDCl₃): δ=98.73 C-1′ (J_(CH)=172.5 Hz), 98.35C-1′ (J_(CH)=171.8 Hz).

Example 18 Syntheses of Building Blocks E-D-1 to E-D-12

Example 18: Syntheses of disaccharides E-D-1 to E-D-12, conditions: a)SOP 32a/b for X=SMe/SCres or SOP 33 for X=OTCA, (88% for E-D-1 via E-1,84% for E-D-4 via E-5, as (α/ β mixtures), b) 1. SOP 9; 2. SOP 25a, (90%for E-D-7 over 2 steps).

Preparation of E-D-1:Methyl(2-azido-6-O-benzoyl-3,4-di-O-benzyl-2-deoxy-β-D-glucopyranosyl)-(1→4)-tert-butyldiphenylsilyl2,3-di-O-benzyl-β-D-glucopyranosid)uronote

A mixture of 2-azido-6-O-benzoyl-2,3di-O-benzyl-2-deoxy-α/β-D-glucopyranosyl trichloroacetimidate (2.5 g,3.94 mmol), and methyl (tert-butyldiphenylsilyl2,3-di-O-benzyl-β-D-glucopyranoside)uronote (1.6 g, 2.55 mmol) andmolecular sieves 4 A (2.5 g) in 50 mL diethyl ether was treated withTBDMSOTf (180 μl, 788.76 μmol) at −20° C. for 1 h. The reaction wasquenched filtered, concentrated and the residue purified by silica gelcolumn chromatography to obtain the desired disaccharide 2.48 g, 88%.R_(f)=0.67 (toluene/ethyl acetate 9/1).

Compound E-D-1:

E-D-1 was formed according to SOP 33 with ether as solvent at −30° C.and TBDMSOTf as promoter in 86% yield (α/β-mixture).

¹H-NMR (400 MHz, CDCl₃): δ=8.00 (m, 2H, Aryl), 7.68 (m, 4H, Aryl), 7.56(m, 1H, Aryl), 7.42 (m, 4H, Aryl), 7.36-7.17 (m, 24H, Aryl), 5.47 (d,1H, J_(1,2)=3.8 Hz, H-1′α), 5.02 (d, 1H, J_(gem)=11.4 Hz, OCH₂), 4.97(d, 1H, J_(gem)=11.0 Hz, OCH₂), 4.84 (m, 4H, OCH₂), 4.75 (d, 1H,J_(gem)=11.4 Hz, OCH₂), 4.66 (d, 1H, J_(1,2)=7.5 Hz, H-1β), 4.57 (d, 1H,J_(gem)=10.9 Hz, OCH₂), 4.45 (m, 2H, H-6′α, H-6′b), 4.15 (dd, J=8.8 Hzand J=9.6 Hz), 3.86 (m, 1H), 3.65 (s, 3H, OCH₃, 3.68-3.58 (m, 3H), 3.55(d, 1H, J_(4,5)=10.0 Hz, H-5), 3.31 (dd, 1H, J_(2,3)=10.2 Hz, H-2′),1.12 (s, 9H, C(CH₃)₃).

Compound E-D-4:

E-D-4 was formed according to SOP 33 with ether as solvent at −30° C.and TBDMSOTf as promoter in 84% yield (α/β-mixture).

Selected ¹H-NMR (400 MHz, CDCl₃): δ=10.02 (dd, 1H, J_(NH,═C—H)=14.4 Hz,J_(NH,H-2)=9.6 Hz, N—H), 8.02 (m, 2H, Aryl), 7.79 (d, 1H, ═C—H),7.72-6.93 (m, 33H, Aryl), 5.60 (d, 1H, J_(1,2)=3.6 Hz, H-1α), 4.49 (d,1H, J_(1,2)=7.8 Hz, H-1β), 3.66 (s, 3H, OCH₃), 3.29 (s, 3H, NCH₃), 3.28(s, 3H, NCH₃), 1.14 (s, 9H, C(CH₃)₃).

Preparation of E-D-7: Methyl(2-azido-6-O-benzoyl-3,4-di-O-benzyl-2-deoxy-α-D-glucopyranosyl)-(1→4)-2,3-di-O-benzyl-β-D-glucopyranosyltrichloroacetimidyl)uronote

A solution of methyl(2-azido-6-O-benzoyl-3,4-di-O-benzyl-2-deoxy-α-D-glucopyranosyl)-(1→4)-tert-butyldiphenylsilyl2,3-di-O-benzyl-β-D-glucopyranoside) uronate (2.09 g, 1.90 mmol) inacetic acid (1.74 mL, 30.45 mmol) and 1 M solution oftetrabutylammoniumfluoride (7.6 mL, 7.61 mmol) was stirred at roomtemperature overnight. The reaction mixture was then concentrated andthe residual syrup was purified by silica gel column chromatography toobtain the desired hemiacetal.

Yield: 1.57 g (95.8%), R_(f)=0.21 (toluene/ethyl acetate 9/1).

A mixture of methyl(2-azido-6-O-benzoyl-3,4-di-O-benzyl-2-deoxy-α-D-glucopyranosyl)-(1-4)-2,3-di-O-benzyl-β-D-glucopyranosyl)uronote (594 mg, 690.70 μmol), trichloroacetonitrile (280 μl, 2.74 mmol)and DBU (31 μl, 209.3 μmol) in 8.0 mL dichloromethane was stirred at 0°C. for 1 h. The mixture was then concentrated and purified on a shortcolumn of silica gel to obtain the title compound as an amorphous whitesolid. Yield: 662 mg (95.3%), R_(f)=0.46 (toluene/ethyl acetate 9/1).

Compound E-D-7:

Selected ¹H-NMR (400 MHz, CDCl₃): δ=8.68 (s, 1H, C═NH), 8.00 (m, 2H,Aryl), 7.56 (m, 2H, Aryl), 7.43-7.23 (m, 22H, Aryl), 6.48 (d, 1H,J_(1,2)=4.3 Hz, H-1α), 5.59 (d, 1H, J_(1,2)=3.6 Hz, H-1′α), 5.03 (1H,J_(gem)=10.8 Hz, OCH₂), 4.93-4.83 (m, 4H, OCH₂), 4.70 (d, 1H,J_(gem)=12.0 Hz, OCH₂), 4.64 (d, 1H, J_(gem)=12.0 Hz, OCH₂), 4.60 (d,1H, J_(gem)=11.2 Hz, OCH₂), 4.47 (m, 2H, H-6′a, H-6′b), 4.42 (m, 1H, notassigned), 4.15 (m, 2H, not assigned), 3.97 (dd, 1H, J=8.2 Hz and J=10.2Hz, not assigned), 3.80 (m, 1H, not assigned), 3.76 (m, 3H, OCH₃),3.72-3.64 (m, 2H, not assigned), 3.30 (dd, 1H, J_(2,3)=10.4 Hz, H-2′).

Example 19 Syntheses of Disaccharides E-D-13 to E-D-44

Example 19: Syntheses of disaccharides E-D-13 to E-D-44, conditions: a)SOP 32a/b for X=SMe/SCres or SOP 33 for X=OTCA (70% for E-D-23, α/βmixture); b) 1. SOP 9; 2. SOP 25a.

Compound E-D-27:

E-D-27 was formed according to SOP 33 with ether as solvent at −20° C.and TBDMSOTf as promoter in 70% yield (α/β-mixture). Selected ¹H-NMR(400 MHz, CDCl₃): δ=7.58 (m, 2H, Aryl), 7.54 (m, 2H, Aryl), 7.36-7.00(m, 23H, Aryl), 6.73 (m, 2H, Aryl), 5.37 (d, 1H, J_(1,2)=3.9 Hz, H-1′α),5.12 (dd, 1H, J_(2,3)=8.8 Hz, H-2), 4.63 (d, 1H, J_(gem)=11.2 Hz, OCH₂),4.58 (d, 1H, J_(gem)=11.2 Hz, OCH₂), 4.48 (d, 1H, J_(1,2)=7.3 Hz, H-1β),3.66 (s, 3H, OCH₃), 3.55 (s, 3H, OCH₃), 3.34 (m, 1H), 3.22 (dd, 1H,J=3.4 Hz, J=10.7 Hz), 1.81 (s, 3H, Oac), 0.98 (s, 9H, C(CH₃)₃).

Example 20 Synthesis of Alternative E-D-Disaccharides E-D-45 to E-D-50

Example 20: Synthesis of alternative E-D-disaccharides E-D-45 to E-D-50,conditions: a) SOP 32a/b for X=SMe/SCres or SOP 33 for X=OTCA, diethylether, TBDMS-Otf, −20 deg. C. (75% for E-D-45 as (α/β-mixture).

Example 21 Synthesis of Trisaccharides E-D-C-1 to E-D-C-16

Example 21: Synthesis of trisaccharide E-D-C-1 to E-D-C-16, conditions:a) SOP 33, (70% for E-D-C 15 as an α/β mixture).

Compound E-D-C-15:

E-D-C-15 was formed according to SOP 33 with dichloromethane as solventat 0 to 20° C. and TBDMSOTf as promoter in 70% yield (α/β-mixture).

¹H-NMR (400 MHz, CDCl₃): δ=7.93 (m, 2H, Aryl), 7.87 (m, 2H, Aryl), 7.66(m, 2H, Aryl), 7.61 (m, 2H, Aryl), 7.46 (m, 2H, Aryl), 7.38-6.99 (m,32H, Aryl), 6.79 (m, 2H, Aryl), 5.27 (d, 1H, J_(1,2)=3.8 Hz, H-1″α),4.99 (dd, 1H, J_(3,4)≈J_(2,3)=9.5 Hz, H-3), 4.80-4.69 (m, 6H, OCH₂),4.52 (m, 3H, OCH₂), 4.40 (d, 1H, J_(1,2)=8.0 Hz, H-1β), 4.38-4.32 (m,2H, not assigned), 4.29 (d, 1H, J_(1,2)=7.5 Hz, H-1β), 4.15 (m, 1H,J_(gem)=12.0 Hz, OCH₂), 4.02 (dd, 1H, J_(4,5)=9.6 Hz, H-4), 3.80 (2 dd,2H, H-3″, H-4′), 3.71, (s, 3H, OCH₃), 3.67 (m, 1H, not assigned),3.61-3.53 (m, 2H, H-5′, H-2′), 3.46 (dd, 1H, J_(gem)=11.2 Hz,J_(5,6a)=2.4 Hz, H-6a), 3.41 (dd, 1H, J_(2,3)≈J_(3,4)=9.0 Hz, H-3′),3.27 (s, 3H, OCH₃), 3.21 (dd, 1H, J_(2,3)=10.0 Hz, H-2″), 3.14 (dd, 1H,H-2′), 3.00 (dd, 1H, J_(5,6b)<2.0 Hz, H-6b), 2.75 (m, 1H, H-5) 1.05 (s,9H, C(CH₃)₃).

Example 22 Synthesis of Trisaccharides E-D-C-17 to E-D-C-32

Example 22: Synthesis of trisaccharide E-D-C-17 to E-D-C-32, conditions:a) SOP 33.

Example 23 Formation of Trisaccharidic Trichloroacetimidates E-D-C-33 toE-D-C-48

Example 23: Formation of trisaccharidic Trichloroacetimidates E-D-C-33to E-D-C-48, conditions: a) 1. SOP 9; 2. SOP 25, (82% over 2 steps forE-D-C-47

Example 24 Syntheses of Trisaccharides E-D-C-9 to E-D-C-12 and E-D-C-49to E-D-C-60

Example 24: Syntheses of trisaccharides E-D-C-9 to E-D-C-12 and E-D-C-49to E-D-C-60, conditions: a) 1. SOP 33; 2. SOP 24; b) SOP 33, (for D-C-5:70%, 2 steps); b) SOP 33, (78% for E-D-C-9 as an α/βmixture).

Compound D-C-5:

D-C-5 was formed according to SOP 33 with ether as solvent at −20° C.and TMSOTf as promoter, followed by SOP 24 in 70% yield (over 2 steps asα/β-mixture).

Selected ¹H-NMR (400 MHz in CDCl₃): δ=7.88 (m, 2H, Ar), 7.67-7.58 (m,5H, Ar), 7.42 (m, 2H, Ar), 7.37-7.12 (m, 16H, Aryl), 6.84 (m, 3H, Ar),5.14 (dd, 1H, J_(1,2)=8.2 Hz, J_(2,3)=9.5 Hz, H-2′), 4.90 (d, 1H,J_(gem)=10.7 Hz, OCH₂), 4.73 (d, 1H, J_(gem)=11.5 Hz, OCH₂), 4.65 (d,1H, J_(1,2)=8.2 Hz, H-1′β), 4.63-4.58 (m, 2H, OCH₂), 4.51 (d, 1H,J_(gem)=12.0 Hz, OCH₂), 4.20 (d, 1H, J_(1,2)=7.9 Hz, H-1β), 4.05 (d, 1H,J_(gem)=11.9 Hz, OCH₂), 4.02-3.95 (m, 2H, not assigned), 3.81 (s, 3H,OCH₃), 3.80 (s, 3H, OCH₃), 3.71 (d, 1H, J_(4,5)=9.9 Hz, H-5′), 3.67 (s,3H, OCH₃), 3.47-3.40 (m, 3H, not assigned), 3.21 (dd, 1H, J=9.0 Hz,J=9.8 Hz, not assigned), 3.00 (dd, 1H, J_(5,6b)=1.4 Hz, J_(gem)=10.5 Hz,H-6b), 2.63 (m, 1H, H-5), 2.35 (bs, 1H, 4-OH), 1.07 (s, 9H, C(CH₃)₃).

Compound E-D-C-9:

E-D-C-9 was formed according to SOP 33 with ether as solvent at −20° C.and TBDMSOTf as promoter in 78% yield (α/β-mixture).

Selected ¹H-NMR (400 MHz, CDCl₃): δ=7.77 (m, 2H, Aryl), 7.59, 7.54 (2m,2×2H, Aryl), 7.35-7.00 (m, 30H, Aryl), 6.88 (m, 2H, Aryl), 6.82 (m, 2H,Aryl), 6.73 (m, 2H, Aryl), 5.41 (d, 1H, J_(1,2)=3.5 Hz, H-1′α), 5.19(dd, 1H, J_(2,3)≈J_(1,2)=9.6 Hz, H-2′), 4.85-4.78 (m, 4H, OCH₂), 4.67(m, 2H, OCH₂), 4.65 (d, 1H, J_(1,2)=8.5 Hz, H-1β, not assigned), 4.38(d, 1H, J_(gem)=11.1 Hz, OCH₂), 4.29 (d, 1H, J_(gem)=11.7 Hz, OCH₂),4.17 (dd, 1H, not assigned), 4.11 (d, 1H, J_(1,2)=7.9 Hz, H-1β notassigned), 4.03 (d, 1H, J_(gem)=12.0 Hz, OCH₂), 3.90-3.76 (m, 3H, notassigned), 3.730, 3.727 (2s, 2×3H, OCH₃), 3.65 (s, 3H, OCH₃), 3.54 (s,3H, OCH₃), 2.89 (dd, 1H, J_(gem)=10.5 Hz, J_(5,6b)<2.0 Hz, H-6b), 2.52(m, 1H, H-5), 1.02 (s, 9H, C(CH₃)₃).

Example 25 Synthesis of Trisaccharides E-D-C-41 E-D-C-42 and E-D-C-61 toE-D-C-66

Example 25: Synthesis of trisaccharides E-D-C-41, E-D-C-42 and E-D-C-61to E-D-C-66, conditions: a) 1. SOP 39; 2. SOP 38; 3. SOP 16; b) 1. SOP14; 2. SOP 25a.

Example 26 An Alternative Route to the Trisaccharides E-D-C-61 andE-D-C-43

Example 26: An alternative route to the trisaccharides E-D-C-61 andE-D-C-63, conditions: a) 1. SOP 39; 2. SOP 38; 3. SOP 16; 4. Pd(Ph₃P)₄,p-TolSO₂Na, THF, MeOH; b) SOP 33.

Example 27 Syntheses of Blocks E-D-C-67 to E-D-C-70

Example 27: Syntheses of trisaccharides E-D-C-67 to E-D-C-70,conditions: a) SOP 33; b) SOP 24; c) SOP 33; d) 1. SOP 36; 2. SOP 37.

Example 28 Synthesis of Trisaccharides E-D-C-70 and E-D-C-71

Example 28: Synthesis of trisaccharides E-D-C-70 and E-D-C-71,conditions: a) SOP 33, (55% for E-D-C-71, α/β mixture).

Compound E-D-C-71:

E-D-C-71 was formed according to SOP 33 with dichloromethane as solventat 40° C. and TBDMSOTf as promoter in 55% yield (as α/β-mixture).

Selected ¹H-NMR (400 MHz, CDCl₃): δ=7.91 (m, 2H, Aryl), 7.61 (m, 2H,Aryl), 7.55 (m, 2H, Aryl), 7.50-7.02 (m, 29H, Aryl), 6.65 (m, 4H, Mp),5.38 (d, 1H, J_(1,2)=3.9 Hz, H-1″α), 5.22 (bs, 1H, NH), 4.67 (d, 1H,J_(1,2)=7.4 Hz, H-1β, not assigned), 4.50 (d, 1H, J_(1,2)=7.8 Hz, H-1β,not assigned), 3.92 (d, 1H, J_(4,5)=9.8 Hz, H-5′), 3.698 (s, 3H, OCH₃),3.693 (s, 3H, OCH₃), 1.03 (s, 9H, C(CH₃)₃).

M_(found)=1408.52 (M+H₂O)⁺, M_(calc)=1390.54 (M⁺).

Example 29 Syntheses of Trisaccharides E-D-C-61, E-D-C-72 and E-D-C-73

Example 29: Syntheses of trisaccharides E-D-C-72 to E-D-C-73 andE-D-C-61, conditions: a) SOP 33; b) SOP 24; c) SOP 33.

Example 30 Syntheses of Trisaccharides C-B-A-1 to C-B-A-4

Example 30: Syntheses of trisaccharides C-B-A-1 to C-B-A-4, conditions:a) SOP 33; b) SOP 32a; c) 1. SOP 27; 2. SOP 20; 3. SOP 16; 4. SOP 24.

Example 31 Synthesis of Trisaccharides C-B-A-5 to C-B-A-8

Example 31: Synthesis of trisaccharides C-B-A-5 and C-B-A-8, conditions:a) SOP 33, (50% for C-B-A-5, α/β mixture).

Compound C-B-A-5:

C-B-A-5 was formed according to SOP 33 with ether as solvent at −20° C.and TBDMSOTf as promoter in 50% yield (as α/β-mixture).

M_(found)=1269.65 (M+H+ H₂O)⁺, M_(calc)=1250.43 (M⁺).

Example 32 Syntheses of D-C-B Trisaccharides D-C-B-1 to D-C-B-3

Example 32: Syntheses of D-C-B-trisaccharides D-C-B-1 to D-C-B-3,conditions: a) 1. SOP 33; 2. SOP 36; 3. SOP 37.

Example 33 Syntheses of D-C-B Trisaccharides D-C-B-4 to D-C-B-7

Example 33: Syntheses of D-C-B-trisaccharides D-C-B-4 to D-C-B-7,conditions: a) 1. SOP 33; 2. SOP 36; 3. SOP 37.

Example 34 Syntheses of Tetrasaccharides D-C-B-A-1 to D-C-B-A-2

Example 34: Syntheses of tetrasaccharides D-C-B-A-1 and D-C-B-A-2,conditions: a) SOP 32a; b)1. SOP 36; 2. SOP 37; 3. SOP 24.

Example 35 Alternative Syntheses of Tetrasaccharides D-C-B-A-2

Example 35: Alternative synthesis of tetrasaccharide D-C-B-A-2,conditions: a) 1. SOP 34; 2. SOP 24.

Example 36 Syntheses of Tetrasaccharides D-C-B-A-3 to D-C-B-A-8

Example 36: Syntheses of tetrasaccharides D-C-B-A-3 to D-C-B-A-8,conditions: a) 1 SOP 32b; 2. SOP 24.

Example 37 Syntheses of Tetrasaccharides E-D-C-B-1 to E-D-C-B-4

Example 37: Syntheses of tetrasaccharides E-D-C-B-1 to E-D-C-B-4,conditions: a) SOP 33; b) 1. SOP 36; 2. SOP 37.

Example 38 Syntheses of Blocks E-D-C-B-5 to E-D-C-B-8

Example 38: Syntheses of tetrasaccharides E-D-C-B-5 to E-D-C-B-8,conditions: a) SOP 33; b) 1. SOP 36; 2. SOP 37.

Example 39 Syntheses of E-D-C-B-A Pentasaccharides P-1 and P-2

Example 39: Syntheses of E-D-C-B-A pentasaccharides P-1 and P-2,conditions: a) SOP 34.

Example 40 Synthesis of E-D-C-B-A Pentasaccharides P-3 to P-26

Example 40: Synthesis of E-D-C-B-A pentasaccharide P-3 to P-26,conditions: a) SOP 33 (75% for P-19 as an α/β mixture).

Compound P-19:

P-19 was formed according to SOP 33 with dichloromethane as solvent at−20° C. and TMSOTf as promotor;

M_(found)=2068.76 (M+H+ H₂O)⁺, M_(calc)=2049.74 (M⁺).

Example 41 Alternative Syntheses of E-D-C-B-A Pentasaccharides P-11,P-12, P-19, P-20 and P-27

Example 41: Alternative syntheses of E-D-C-B-A pentasaccharides P-11,P-12, P-19, P-20 and P-27, conditions: a) SOP 32a.

Example 42 Alternative Syntheses of some E-D-C-B-A Pentasaccharides

Example 42: Alternative syntheses of some E-D-C-B-A pentasaccharides,conditions: a) SOP 32a (for R=SCres) or SOP 33 (for R=OTCA).

Example 43 Synthesis of Pentasaccharide P-13 and P-30

Example 43: Formation of pentasaccharides P-13 and P-30, conditions: a)SOP 32a.

Example 44 Formation of Pentasaccharide P-19 and P-31

Example 44: Formation of pentasaccharide P-19 and P-31 conditions: a)SOP 33

Example Preparation of P19

A mixture ofO-(2-azido-6-O-benzoyl-3,4-di-O-benzyl-2-deoxy-α-D-glucopyranosyl)-(1-4)-(methyl2,3-di-O-benzyl-β-D-glucopyranosyluronate)-(1→4)-2-azido-3-O-benzoyl-2-deoxy-6-O-p-methoxybenzyl-α-D-glucopyranosyltrichloroacetimidate(30.0 mg, 21.2 μmol) and methyl (methyl2-O-benzoyl-3-O-benzyl-(α-L-idupyranosyluronate)-(1→4)-2-azido-3-O-benzyl-6-O-benzoyl-2-deoxy-α-D-glucopyranoside(15.4 mg 19.3 μmol) and 100 mg of molecular sieves 4 Å in 1.5 mL drydichloromethane was treated with TBDMSOTf (0.97 μl, 4.24 μmol) at −20°C. for 20 hours. The reaction was quenched, filtered and concentrated.Further purification of the title compound was achieved by silica gelchromatography Yield: 15.83 mg (40%), R_(f)=0.30 (toluene/ethylacetate=9/1).

Example 45 Partial Deprotection of Pentasaccharide P-19

Example 45: Partial deprotection of pentasaccharide P-19, conditions: a)SOP 28, 84%; b) SOP 39, 86%.

Compound P-33:

M_(found)=1503.5 (M-N₂+2H)⁺, M_(calc)=1529.51 (M⁺).

To ease the structural proof, a small part of P-33 was transformed intothe bis methyl uronurate derivative and characterized viaNMR-spectroscopy. Characteristic ¹H-NMR-spectral regions are shown inFIG. 1.

M_(found)=1514.62 (M+H)⁺, M_(calc)=1513.58 (M⁺).

Example 46 Partial Deprotection of Pentasaccharide P-30, Containing aDTPM-Group as Amino Protection

Example 46: Partial deprotection of pentasaccharide P-30, containing aDTPM-group as amino protection, conditions: a) 1. SOP 28; 2. SOP 39;b) 1. SOP 11 with MeNH₂ as primary amine and MeOH as solvent; 2. SOP 12.

Example 47 Partial Deprotection of Pentasaccharide P-1 Containing aCyclic Carbamate as Amino Protection

Example 47: Partial deprotection of pentasaccharide P-1, containing acyclic carbamate as amino protection, conditions: a) SOP 27; b) SOP 39;c) SOP 12.

Example 48 Deprotection Protocol for Pentasaccharides P-37 of claim 4

Example 48: Deprotection protocol for pentasaccharides P-37 of claim 4,conditions: a) 1. SOP 27 and 28; 2. SOP 39; 3. SOP 11 with MeNH₂ asprimary amine and MeOH as solvent; 4. SOP 12.

Example 49 Transformation of Pentasaccharide P-33 into the O- andN-Sulfated Pentasaccharide P-40

Example 49: Transformation of pentasaccharide P-33 into the O- andN-sulfated pentasaccharide P-40, conditions: a) SO₃xNMe₃, DMF, 50° C.;b) H₂ (70 psi), Pd/C, H₂O; c) SO₃× Pyridine, H₂O, pH=9.5. Thetransformation of P-33 into P-40 has been performed according toliterature: Petitou et al., Carbohydr. Res. 1987, 167, 67-75.

The ¹H-NMR (400 MHz, D₂O) of P-40 is shown in FIG. 2.

REFERENCES

-   ¹ Lindahl, U., Backdtrom, G., Thunberg, L., Leder, I. G., Proc.    Natl. Acad. Sci. USA, 1980, Vol. 77, No. 11, 6551-6555; Reisenfeld,    J., Thunberg, L., Hook, M., & Lindahl, U., J. Biol. Chem., 1981,    Vol. 256, No. 5, 2389-2394.-   ² Choay, J., Lormeau, J-C., Petitou, M., Sinay, P., and Fareed, J.,    Annals New York Academy of Sciences, 1981, 370, 644-649.-   ³ Pierre Sinaÿ, Jean-Claude Jacquinet, Carbohydrate Research, 132,    (1984), C₅-C₉.-   ⁴ C. A. A. van Boeckel, T. Beetz, J. N. Vos, A. J. M. de Jong, S. F.    van Aelst, R. H. van den Bosch, J. M. R. Mertens and F. A. van der    Vlugt., J. Carbohydrate Chemistry, 4(3), 1985, 293-321.-   ⁵. J. Choay, M. Petitou, J. C. Lormeau, P. Sinay, J. Fareed, Ann. NY    Acad. Sci., 1981, 370, 644-649.-   ⁶ J Choay et. al., Biochem. Biophys. Res. Commun., 1983, 116,    492-499.

The invention claimed is:
 1. A monosaccharide of General Formula X

in which the ring is of the D-Gluco stereochemistry; wherein X₁ isselected from the group consisting of alpha or beta thiomethyl orthiocresyl or trichloroacetimidoyl or t-butyldiphenylsilyloxy, alphamethoxy; R_(H1) is selected from the group consisting of benzyl orsubstituted benzyl protecting group or R_(H1) and R_(A) can combinetogether to form a cyclic carbamate; R_(A) is selected from the groupconsisting of an azido function, an NH-Dde, NH-DTPM; or R_(H1) and R_(A)can combine together to form a cyclic carbamate; R_(S1) is selected fromthe group consisting of 4-methoxyphenyl; 4-methoxybenzyl, benzoyl, and4-chlorobenzoyl; R_(L) is selected from a hydrogen atom or a levulinoyl.2. The monosaccharide of claim 1, wherein: R_(A) is azido or R_(A) andR_(H1) combine to form a cyclic carbamate.
 3. The monosaccharide ofclaim 1, wherein R_(H1) is benzyl.
 4. A monosaccharide of GeneralFormula XIII,

in which the ring is of the D-Gluco stereochemistry; wherein: R_(S3) isselected from the group consisting of 4-methoxyphenyl; 4-methoxybenzyl,benzoyl, 4-chlorobenzoyl, allyloxycarbonyl and allyl; R_(S4) is selectedfrom the group consisting of 4-methoxyphenyl, 4-methoxybenzyl, benzoyl,4-chlorobenzoyl, and allyl, or R_(S4) and R_(B) may be combined to forma cyclic carbamate; R_(B) is selected from the group consisting of anazido function and an amine, or R_(S4) and R_(B) can combine together toform a cyclic carbamate; R_(L) is selected from the group consisting ofa a hydrogen atom and a levulinoyl group; X₃ is selected from the groupconsisting of a thiomethyl, thioethyl, thiophenyl, thiocresyl,trichloroacetimidoyl, and tert-butyldiphenylsilyloxy; and thestereochemistry may be alpha or beta.
 5. A monosaccharide of GeneralFormula XVI,

wherein: X₁ is selected from the group consisting of thiomethyl,thiocresyl, trichloroacetimidoyl, and a tbutyldiphenylsilyloxy; and thestereochemistry may be alpha or beta; R_(L) is selected from the groupconsisting of a hydrogen atom, a levulinoyl; R_(S6) is selected from thegroup consisting of 4-methoxyphenyl, 4-methoxybenzyl; benzoyl,4-chlorobenzoyl, and tert-Butyldiphenylsilyl.
 6. The monosaccharide ofclaim 1, wherein the monosaccharide is of the formula:


7. The monosaccharide of claim 4, wherein the monosaccharide is of theformula:


8. The monosaccharide of claim 4, wherein the monosaccharide is of theformula:


9. The monosaccharide of claim 4, wherein the monosaccharide is of theformula:


10. The monosaccharide of claim 4, wherein the monosaccharide is of theformula:


11. The monosaccharide of claim 4, wherein the monosaccharide is of theformula:


12. The monosaccharide of claim 4, wherein the monosaccharide is of theformula:


13. A monosaccharide of the formula: